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Expression and function of long non-coding RNAs in head and neck squamous cell carcinoma
Experimental and Molecular Pathology 112 (2020) 104353
Contents lists available at ScienceDirect
Experimental and Molecular Pathology journal homepage: www.elsevier.com/locate/yexmp
Review
Expression and function of long non-coding RNAs in head and neck squamous cell carcinoma Soudeh Ghafouri-Farda, Hossein Mohammad-Rahimib, Marzieh Jazaeric, Mohammad Taherid,
T ⁎
a
Department of Medical Genetics, Shahid Beheshti University of Medical Sciences, Tehran, Iran School of Dentistry, Shahid Beheshti University of Medical Sciences, Tehran, Iran c School of Dentistry, Hamadan University of Medical Sciences, Hamadan, Iran d Urogenital Stem Cell Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran b
ARTICLE INFO
ABSTRACT
Keywords: Long non-coding RNA Head and neck squamous cell carcinoma
No longer regarded as junk DNA, long non-coding RNAs (lncRNAs) are considered as master regulators of cancer development and metastasis nowadays. Among the recently appreciated roles of these transcripts is their fundamental contribution in the pathogenesis of head and neck squamous cell carcinoma (HNSCC). Notably, lncRNAs may have interactions with some environmental risk factors for this type of cancer. Moreover, a number of studies have verified diagnostic and prognostic values of lncRNAs in HNSCC. Emerging evidences from functional studies point to the possibility of design of lncRNA-targeted therapies in HNSCC. In the current review, we discuss the molecular mechanisms for participation of lncRNAs in the pathogenesis of HNSCC, their potential application in cancer diagnosis and most importantly in the development of personalized methods for treatment of HNSCC.
1. Introduction Head and neck squamous cell carcinoma (HNSCC) has an annual rate of 500,000 new cases worldwide (Torre et al., 2015). This type of cancer originates from various anatomic sites including oral cavity, oropharynx, hypopharynx, larynx, nasopharynx, palatine, and lingual tonsils (Marur and Forastiere, 2016a). HNSCC has been associated with some environmental/ life style risk factors including tobacco smoking, alcohol use, and viral infections (Marur and Forastiere, 2008; Sturgis and Cinciripini, 2007). Notably, human papillomavirus (HPV) is regarded as a risk factor for development of oropharyngeal cancer (Sturgis and Cinciripini, 2007). Surgery or radiotherapy, combination of surgery with adjuvant radiation or chemoradiation, and chemotherapy with or without a biological drug are recommended for early stage, locally advanced and metastatic disease, respectively (Marur and Forastiere, 2016b). Based on such trend in the complexity of treatment modalities as the disease progresses, early detection of HNSCC has clinical importance. For such purpose, identification of molecular pathways which are involved in each step of cancer progression is a critical necessity. Recent studies have highlighted the role of a group of transcripts namely long non-coding RNAs (lncRNAs) in the pathogenesis of diverse cancers including HNSCC (Guglas et al., 2017). This group of transcripts has no obvious open reading frame to produce
⁎
functional proteins, yet regulating gene expression at several levels and are implicated in the evolution and progression of human cancers (Sanchez Calle et al., 2018). A well-known mechanism for their involvement in the pathogenesis of cancer is their function as miRNAs sponges to decline effects of miRNAs on the mRNAs (Deng et al., 2015). LncRNAs participating in the carcinogenesis process were mainly associated with cellular macromolecules such as chromatin, protein and other types of RNA molecules (Huarte, 2015; Zhang et al., 2019b). Fig. 1 depicts a summary of cellular pathways influenced by lncRNAs in HNSCC. In the present review, we summarize recent findings regarding the role of lncRNAs in the pathogenesis of HNSCC. 2. Expression of lncRNAs in HNSCC LncRNAs can be classified to oncogenic and tumor suppressor transcripts based on their expression pattern in tumoral tissues versus non-tumoral tissues of the same origin and functions in regulation of cell cycle, apoptosis and cell proliferation. Several studies have shown up-regulation of numerous lncRNAs in cell lines or patients’ sample of HNSCC origin. Table 1 summarizes the information about these upregulated lncRNAs which are putative oncogenic lncRNAs. The mostly assessed lncRNA in HNSCC is MALAT1. Several studies have reported
Corresponding author. E-mail address: [email protected] (M. Taheri).
https://doi.org/10.1016/j.yexmp.2019.104353 Received 12 October 2019; Received in revised form 25 November 2019; Accepted 4 December 2019 Available online 05 December 2019 0014-4800/ © 2019 Elsevier Inc. All rights reserved.
Experimental and Molecular Pathology 112 (2020) 104353
S. Ghafouri-Fard, et al.
Fig. 1. (A) GAS5 acts as a tumor suppressor in Oral SCC. This lncRNA exerts its function through suppression of miR-21 and subsequent up-regulation of PTEN (Zeng et al., 2019). Reduced level of GAS5 leads to increased levels of miR-21 and inhibition of PTEN. (B) LncRNA PTCSC3 suppresses cell proliferation in laryngeal SCC through down-regulation of lncRNA HOTAIR. This effect is probably exerted through down-regulation of STAT3 (Xiao et al., 2019a). (C) Overexpression of the lncRNA MORT suppresses oral SCC cell proliferation by down-regulating ROCK1 (Jin et al., 2019). (D) NKILA suppresses the epithelial-mesenchymal transition (EMT) process through obstruction of the phosphorylation of IκBα and NF-κB induction (Huang et al., 2016).
up-regulation of this lncRNA in oral SCC samples and verified its role in enhancement of cell proliferation, anchorage-independent growth and migration as well as inhibition of apoptosis. Higher levels of this lncRNA have been associated with lymph node metastasis and poor survival of cancer patients (Han et al., 2019; Fang et al., 2016). Consistent with the acknowledged competing endogenous (ce) RNA role for lncRNAs, functional assays have identified several lncRNA-miRNA pairs whose interactions alter the carcinogenesis process. Besides, aberrant expression of lncRNAs has been associated with dysregulation of Wnt/ β-catenin, PI3K/Akt and NF-κB signaling pathways in cancerous tissues. A number of lncRNAs have been shown to be down-regulated in HNSCC samples and cell lines compared with non-cancerous cells (Table 2). Generally, down-regulation of these lncRNAs has been associated with poor survival of cancer patients. These lncRNAs are also involved in the regulation of cell cycle progression, cell proliferation and apoptosis. Among the most evaluated tumor suppressor lncRNAs are CASC2 and MEG3. A recent study has shown down-regulation of CASC2 in oral SCC samples in association with adverse clinicopathological features. Functional studies have shown that forced overexpression of this lncRNA suppresses cell proliferation partially via enhancement of cell apoptosis and induction of cell cycle arrest. Notably, CASC2 is regarded as a ceRNA for miR-21 to stimulate expression of PDCD4. Tumor suppressor role of this lncRNA has been verified in vivo as well (Pan et al., 2019). MEG3 is another tumor suppressor lncRNA that suppresses cell proliferation, migration and invasion of SCC cells. Function of this lncRNA is exerted at least partly through
sponging miR-4261. The role of MEG3 in suppression of tumor growth has been also verified in animal models (Ma et al., 2019). 3. Correlations between lncRNAs and viral infections in HNSCC Nohata et al. have identified 140 lncRNAs with differential expression between HPV positive tumors and HPV negative ones (Nohata et al., 2016). Ma et al. have shown higher numbers of myeloid-derived suppressor cells (MDSCs) in HPV-positive HNSCC compared with normal controls. Moreover, they have reported 132 distinct lncRNAs in diverse HPV infected states of HNSCC. Notably, HOTAIR, PROM1, CCAT1, and MUC19 levels have been inversely correlated with aggregation of MDSCs in HPV-associated HNSCC (Ma et al., 2017a). 4. Prognostic value of lncRNAs in HNSCC Recently, Yang et al. have proposed a panel of lncRNAs which could predict survival prognosis of HNSCC patients through assessment of RNA-seq data of 269 patients. This panel included AC010624.1, AC130456.4, LINC00608, LINC01300, MIR99AHG, AC008655.1, AC055758.2, and AC118553.1 (Yang et al., 2019a). Another study has evaluated lncRNA expression data in 425 HNSCC patients and reported that three lncRNAs (AC002066.1, AC013652.1 and AC016629.3) were significantly associated with survival in an independent manner from clinical features (Wang et al., 2018a). Nohata et al. have assessed RNAseq data of 426 HNSCC and 42 adjacent normal tissues and have 2
3
Laryngeal SCC
Oral SCC
Tongue SCC
Oral SCC
MIR155HG
CRNDE
LINC00511
FLJ22447
54 OSCC tumor samples; SPF grade Nu/Nu nude mice
72 tumor tissues and ANTs
Human HNSCC Specimens, 4week-old BALB/c-nu mice
30 paired cancer specimens and ANTs
Tongue SCC
HNSCC
Tongue SCC
32 TSCC and paired ANTs
SCC specimens from 52 patients and normal oral mucosa tissue specimens from 25 healthy individuals, BALB/ c-nu mice SCC tissues and corresponding ANTs from 20 patients 10 paired ANTs and tumor tissues; BALB/c-nu/nu T celldeficient mice 41 HNSCC samples from different anatomical sites and peripheral blood sample 94 TSCC tissue specimens and matched ANTs 127 TSCC samples, ANTs and lymph node metastases (if exist), Six-week-old male nude mice 14 OSCC and ANT pairs
30 tumor tissues and paired ANTs 58 patients, 30 specific pathogen free male BALB/c nude mice Tumor samples and ANTs from 45 patients
60 oral SCC specimens and 8 ANTs 60 oral cancer and 8 normal tissue samples OSCC tissues samples and ANTs from 48 patients
Samples
Oral SCC
Oral SCC
Tongue SCC
Tongue SCC
Tongue SCC
Oral SCC
LINC01116
MALAT-1
Tongue SCC
RP5-916L7.2
Tongue SCC
Oral SCC
PLAC2
UCA1
Oral SCC
CCAT1
HNSCC
Oral SCC
Linc-RoR
H19
Cancer subtype
Gene
CAL-27, SCC-9, SCC-4, SCC-15 and SCC-25
SCC15, SCC25, CAL27, HaCaT
SCC4, SCC15, SCC25, Hs 680.Tg
Tca8113, SCC-25, CAL-27, HN5, Hs680.Tg Tscca, Tca8113P160, Tca8113 and Hep-2
SCC-9 and CAL-27
STAT3, miR-30a, E-cadherin, N-cadherin, vimentin, Twist and MMP2/9 miR-124, JAG1
Ki67, MMP2/9, N-cadherin, Vimentin, E-cadherin, βcatenin, NF-κB MMP-9, Akt (phosphorylation), MEG3
miR-125b, STAT3
BAX, vimentin, E-cadherin, DKK1
SPRR1B, SPRR2A, SPRR2E, LAYN, CCT4, CTHRC1, and FHL1
CAL27 and SCC-25
SSC4
MALAT-1, MEG3
IGF2, CCCTC-binding factor, p57KIP2
IL-33
miR-765, LAMC2
E-cadherin, p-GSK-3β, βcatenin, N-cadheri, vimentin and Snail protein
miR-155-5p
miR-136
miR-328-5p and miR-939-5p
p53, c-Myc, Klf4, Oct4, Sox2, miR-145-5p c-Myc, miR155-5, let7b-5p, miR218-5, miR490-3p H3K27ac
Gene interaction
Tca8113
-
HOEC cells, Tca-8113, SCC-9, SCC-4 and CAL-27 HSC-3
Immortalized HOK cells, Tca8113, SCC-9, TSCCA, CAL27 and SCC-15
TU686, TU177, AMC-HN-8, 293T cells
SciL-0682, Tca83, TSCC, NB, NT
Tca-8113
SCC-9, CAL-27
-
Assessed cell line
Table 1 Function of up-regulated lncRNAs in HNSCC (ANT: adjacent normal tissue, EMT: epithelial-mesenchymal transition).
MALAT1/miR-124/JAG1
STAT3/malat1/miR-30a
PI3K/Akt
β-catenin and NF-κB
MALAT1/miR-125b/STAT3
Wnt/b-catenin
-
-
-
-
LINC00511/miR-765/ LAMC2 LncRNA-CAF/IL-33
Wnt/β-catenin
miR-155-5p/SOX10
LINC01116/miR-136/FN1
-
Wnt/β-catenin
P53 signal pathway
Signaling pathways
-
Poor Prognosis
Poorer overall survival
Poor prognosis
-
-
-
Lymph node metastasis -
Tumor recurrence
Poor prognosis
-
Poor prognosis, lymph node metastasis Poor prognosis
Poor prognosis
Poor prognosis, tumor size, TNM stage -
Poor prognosis
-
Association with patient outcome
(Zhang et al., 2017)
(Wang et al., 2018d)
(Yuan et al., 2019b)
(Chang and Hu, 2017) (Zhou et al., 2015)
(Liang et al., 2017a)
(Han et al., 2019)
(Fang et al., 2014) (Fang et al., 2016)
(Esteves et al., 2005)
(Ding et al., 2018a) (Ding et al., 2018b)
(Dai et al., 2019)
(Cui et al., 2019a)
(Chen et al., 2019b) (Chen et al., 2019c)
(Arunkumar et al., 2017a) (Arunkumar et al., 2017b) (Chen et al., 2019a)
Ref.
(continued on next page)
Cell proliferation, apoptosis, anchorage-independent growth, migration Lymph node metastasis, cell migration, invasion, EMT, apoptosis Metastasis, Cell proliferation, Apoptosis Tumor growth and metastasis, cell migration and invasion, EMT Cell proliferation, migration and invasion, distant metastasis EMT, metastasis, HNSCC outgrowth, proliferative capacity, tumor size Cell growth, proliferation, invasion, metastasis
Metastasis
Cell migration
Cell proliferation, Cell cycle distribution and invasion Cell proliferation, Migration and therapy-induced apoptosis
Cell proliferation, Migration, Invasion, EMT and apoptosis
Cell proliferation, migration, invasion
Cell proliferation, invasion and migration
Cells proliferation, Apoptosis
Cell cycle transition, Cell proliferation, Cell migration Cell proliferation, Migration, Invasion,
Cell proliferation, metastasis
Functions
S. Ghafouri-Fard, et al.
Experimental and Molecular Pathology 112 (2020) 104353
4
Oral SCC
HNSCC
nasopharyngeal carcinoma Oral SCC
Oral SCC
HNSCC
Laryngeal SCC
-
HNSCC
Oral SCC
Oral SCC
Tongue SCC
Laryngeal SCC
CEBPA-AS1
LINC00473
LncRNA-ROR
NEAT1
LINC00958
MIR100HG
CCAT1
ZFAS1
FOXCUT
LUCAT1
H19
HOTAIR
WWTR1-AS1
HNSCC
HNSCC
HNSCC
H19
H1
Laryngeal SCC
SNHG1
72 patients; Hep-2 cell line, BALB/c mice Athymic female nude mice
50 Paired OSCC tissues and ANTs 16 patients
23 OSCC tissue specimens with matched ANTs
NOD-SCID Gamma (NSG) mice
70 tumor and ANTs
42 freshly frozen OSCC tissues, as well as 42 matched controls, BALB/c nude mice 30 OSCC tissues and their ANTs; Ten female athymic BALB/c nude mice 48 cases of paired HNSCC and ANTs
78 paired of clinical HNSCC and matched ANTs BALB/c nude mice
60 pairs of OSCC tissues and matched ANTs
62 HNSCC samples and ANTs from 19 samples
65 matched cancerous and ANTs
40 TSCC tissues and ANTs; Nu/ Nu nude mice 30 OSCC tumor tissues and ANTs, BALB/c nude mice
Tongue SCC
Oral SCC
Samples
Cancer subtype
UCA1
Gene
Table 1 (continued)
Tu686, TSCCA and Cal27, Tb3.1, HIOEC
Tca8113, OSC-4, SCC1, SCC2, SCC4, SCC9, CAL-27, UM1, UM2, SMMC7721, HCCLM3, HUH7, HEPG2, MCF7, BT474, SKBR3, HCC1187, HCC1143, LO2, HOK, MCF-10A Tca8113, TSCCA, CAL-27, SCC-9, NHOK CAL27, SCC9, SCC15, SCC25, and FaDu Hep-2
DOK, SCC-040, SCC-25, FaDu
KYSE, TE-5 and TT, UMSCC1, 93UV147, SK-MES-1, Calu-1, ChagoK1, H520, H2170, H226
HOK, HEK-293T, Detroit 562, Cal27, SCC-9, SCC-15, and Fadu UM-SCC-17A,
hNOK, SCC-9, SCC-25, HN4, Tca-8113 and Cal-27
SCC9, SCC15, SCC25, and CAL2, OKC NP69, CNE-1, CNE-2, HONE-1, HNE-1 SCC-4, SCC-15, CAL-27, HSC-3, HSC-2, Ca9-22, HOK-16B
STC2, miR-206
miR-let-7, HMGA2, vimentin, N-cadherin, twist, zeb1, snail1 PTEN
PI3K/AKT, HOTAIR/miR206/STC2 WWTR1-AS1/WWTR1
-
H19/let-7a/HMGA2
-
FOXC1/FOXCUT
FOXC1, MMP2, MMP7, MMP9, VEGF-A
PCNA
Cadherin, integrin, EGFR, FAS, FGF, insulin/IGF, TGFβ, VEGF, interleukin, JAK/ STAT, PDGF, PI3K, p53, p38, Ras, Toll receptor, Wnt
TP63/SOX2-CCAT1-EGFR, MEK/ERK1/2, PI3K/AKT
MIR100HG/ miR-204-5p
LINC00958/c-Myc
NEAT1/miR-365/RGS20
H19/miR-138/EZH2
LncRNA-ROR/P53
Wnt/β-catenin
CEBPA-AS1/CEBPA/Bcl2
H19/miR-675
miR-375/YAP1/Hippo
UCA1/miR-184
miR-140-5p/PAK1
Signaling pathways
ZNFX1, miR-150-5p, EIF4E
TP63, SOX2, EGFR, ETV4, TXNRD1, CDK4, YES1, PAK4, HMGA1
miR-204-5p
miR-365, RGS2, cyclin D1, Ecadherin, N-cadherin, vimentin c-Myc
miR-138, EZH2, vimentin, Ncadherin, ZEB1, E-cadherin
P53
Bax protein, Bcl-2 protein
CEBPA, Bcl2
miR-675, Slug, HuR, EGR1
Hep-2, iNOE Tca8113 and Cal27, hNOK
YAP1, miR-375
miR-140-5p, PAK1, miR-503, miR-96 miR-184, SF1, caspase-3, Bax protein, BCL2
Gene interaction
NHOKs, Tca8113, SCC-2, SCC4, SCC-9, and Cal-27 Tca8113, SCCA, CAL-27, SCC9, NHOK, Tca8113-CDDP and TSCCA-CDDP AMC-HN-8 and Hep-2
Assessed cell line
-
Poor prognosis
Poor prognosis
-
-
Poor prognosis
-
-
Poor prognosis
Poor prognosis
Poor prognosis
Poor prognosis
Poor prognosis, lymph node metastases Poor prognosis, lymph node metastasis Poor prognosis
Poor prognosis
-
-
Association with patient outcome
(Li et al., 2019d)
(Kong et al., 2019) (Kou et al., 2019) (Li et al., 2013)
(Kong et al., 2014)
(Kolenda et al., 2019)
(Huang et al., 2019b) (Jiang et al., 2018)
(Huang et al., 2019a)
(Huang et al., 2018)
(Han et al., 2018) (Hong et al., 2019) (Hong et al., 2018)
(Guo et al., 2018)
(Guan et al., 2016)
(Gao et al., 2018)
(Zhu et al., 2019) (Fang et al., 2017)
Ref.
(continued on next page)
Cell apoptosis, invasion, tumor Growth Cell proliferation, invasion, migration, tumor growth
Cell growth, migration, and invasion Cell migration and invasion
Cell proliferation, invasion, apoptosis, cell cycle control, EMT Cell viability, colony formation, resistance to chemo- and radiotherapy Cell proliferation, migration and invasion Cell-cycle regulation, chromatin binding, cell proliferation, survival, metastasis EMT, proliferation, migration, invasion, apoptosis, cell adhesion, signal transduction, differentiation, angiogenesis, oxidative stress response EMT and cell migration
Cell proliferation, migration and invasion, Tumor growth
Cell proliferation, apoptosis, radio resistance of HNSCC Cell proliferation, apoptosis
Cells proliferation, apoptosis, migration and invasion
Cell proliferation, migration, and invasion, tumor growth Cell proliferation, CDDP sensitivity in OSCC, Tumor growth Cell proliferation, migration and invasion apoptosis, tumor growth, metastasis Cell proliferation, viability, migration, invasion
Functions
S. Ghafouri-Fard, et al.
Experimental and Molecular Pathology 112 (2020) 104353
5
Oral SCC
Oral SCC
Oral SCC
Oral SCC
Oral SCC
Oral SCC
Oral SCC
FTH1P3
TUG1
NEAT1
HNF1A-AS1
MINCR
CCAT2
Oral SCC
TUG1
ANRIL
Laryngeal SCC
snaR
Oral SCC
Tongue SCC
TUG1
HOTAIR
Laryngeal SCC
External auditory canal SCC
Tongue SCC
ADAMTS9AS2 SNHG20
lnc-MMP3-1
Oral SCC
AC132217.4
Tongue SCC
Oral SCC
SNHG16
CILA1
Oral SCC
LINC00152
Laryngeal SCC
Oral SCC
OIP5-AS1
SNHG1
Cancer subtype
Gene
Table 1 (continued)
62 paired OSCC tissues and ANTs
62 pairs of OSCC tissues and their ANTs OSCC tissues and paired ANTs
58 OSCC and ANTs
BALB/c thymic free nude mice
134 patients
56 tissue and serum samples
-
8 pairs of cancerous and ANTs
155 patients; BALB/c-nu mice
20 pairs of carcinoma tissues and ANTs
56 pairs of LSCC tissues and ANTs 27 samples of fresh TSCC tissues and ANTs 52 patients with LSCC and 38 healthy volunteers 96 OSCC tissues and matched ANTs
Tca8113, Cal27, and hNOK
CAL-27, HN5, SCC-15, SCC-9, Tca8113, NHO TSCCA, Tca8113, SCC25, HOK
HN4, Tca-8113, UM-SCC-1, Cal-27, SCC-25, SCCKN, hNOK
SNU1041, SCC25, SCC4, SCC9, hNOK NOK, SCC-4, SCC-9, SCC-25, CAL-27, HN-6, and TCA8113
SCC15, TW2.6
Tca8113
-
CAL27 and SCC9
HEp-2
NHOK, SCC-25, CAL-27, Tca8113, and TSCCA
UM-SCC-17A
CAL-27 and SCC-9
Cal27, SCC9, SCC15, SCC25 and SCC4, NOKs AMC-HN-8 and Hep-2
UM-SCC6, UM-SCC6H, SCC090
SCC-25, CAL-27, NHOK
SCC9, SCC15, Ca9-22, HSU3, NHOK Tca8113, OSCC-15, SCC-9, and SCC-25, hNOKs
SCC4, SCC9, SCC25, FaDu, Cal27, HOK
73 tumor specimens with paired ANTs
38 pairs OSCC tissue samples ANTs, BALB/c nude mice 40 OSCC tissues and corresponding ANTs; BALB/c nude mice 29 pairs of OSCC tissues and normal tissues; Balb/c-nude mice 30 OSCC tissues and normal tissues; Four-week-old nude mice 76 TSCC specimens
Assessed cell line
Samples
STAT3, Jagged-1/Fc, Notch1 and Hes1 β-catenin, cyclin D1, Ecadherin, N-cadherin and cmyc
miR-365, MMP-2, MMP9
miR-524-5p, DLX1
-
Active caspase-3
p53, p21
β-catenin, cyclin D1, cmyc, LiCl, cleaved caspase-3 and caspase-9, Bax, Bcl-2 Bax, Bcl-2, cleaved Caspase-9, cleaved PARP, MMP-2 and MMP-9 E-cadherin, vimentin, Wnt5A, b-catenin, GSK-3b, c-Myc, survivin -
TGF-β1
-
miR-600, EZH2, E-cadherin, vimentin miR-140
c-Myc, PCNA, MMP-2, MMP-9, E-cadherin, N-cadherin, Snail, has-miR-124-3p IGF2, KLF8
miR-139-5p, N-cadheri, Vimentin, E-cadherin
miR-338-3p, NRP1
WWTR1, CD44, CD133, Bmi1, SOX2, E-cadherin, N-cadherin, vimentin, Twist, Slug
Gene interaction
Wnt/β-catenin
Wnt/beta-catenin
Notch
-
PI3K/Akt/GSK3b/ Wnt/bcatenin TUG1/miR-524-5p/DLX1
TGF-β/Smad
Pathways in cancer, PI3KAkt signaling pathway and focal adhesion -
Wnt/b-Catenin
Poor prognosis
Poor prognosis
Poor prognosis, lymph node metastasis Poor prognosis
Poor prognosis, TNM stage -
-
-
Poor prognosis, TNM stage
Poor prognosis
TNM stage, lymph node metastasis, tumor grade Poor prognosis and metastasis
Wnt/β-catenin Mitochondrial apoptotic pathway
Poor prognosis
-
Poor prognosis
Poor prognosis
-
-
Poor prognosis
Unfavorable prognosis, tumor size, cervical node metastasis -
Association with patient outcome
-
-
-
miR-600/EZH2
KLF8/AC132217.4/IGF2
-
-
miR-338-3p/NRP1
Signaling pathways
(Ma et al., 2017b)
(Liu et al., 2019c) (Lyu et al., 2019)
(Liu et al., 2018b)
(Liu et al., 2016) (Liu et al., 2019a) (Liu et al., 2018a) (Liu et al., 2019b)
(Liu et al., 2017a)
(Lin et al., 2018b)
(Lin et al., 2018a)
(Li et al., 2019e) (Liu et al., 2019c) (Liu et al., 2017b) (Liang et al., 2019) (Liang et al., 2017b)
(Li et al., 2017)
(Li et al., 2019c)
(Li et al., 2019b) (Li et al., 2018)
(Li et al., 2019a)
Ref.
(continued on next page)
Cell proliferation, migration, EMT, apoptosis Cell proliferation, migration, cell cycle progression, apoptosis, metastasis Cell proliferation, invasion, inhibiting and apoptosis
Cell proliferation, apoptosis and cell cycle Cell proliferation and apoptosis Cell proliferation, migration and invasion Migratory, proliferative potentials, cell-cycle progression Cell migration and invasiveness
Differentiation degree, tumor invasion
Cell carcinoma proliferation, migration and EMT Cell Proliferation and tumor stage Apoptosis, cell proliferation, cell cycle Cell proliferation, migration, and invasion Cell growth, cell proliferation, cell invasion, colony formation, apoptosis Cell proliferation, invasion, migration, apoptosis, colony formation, EMT Metastasis, EMT, ChemoResistance, cell viability
Cell proliferation, migration and invasion, tumor growth Cell proliferation, colony formation, migration, invasion, EMT, tumor growth Cell proliferation, migration and invasion, cell cycle, apoptosis, tumor growth Metastasis, cell migration and EMT
Cell proliferation, migration, invasion, apoptosis
Functions
S. Ghafouri-Fard, et al.
Experimental and Molecular Pathology 112 (2020) 104353
HNSCC
Laryngeal SCC
Tongue SCC
Oral SCC
Tongue SCC
Laryngeal SCC
SOX2-OT
MPRL
LACAT1
UCA1
HOTAIR
HOXA11-AS
PCAT-1
Laryngeal SCC
RHPN1-AS1
Laryngeal SCC
HNSCC
ST7-AS1
UCA1
Hypopharyngeal SCC Laryngeal SCC
UCA1
Oral SCC
Cutaneous SCC
PICSAR
PDIA3P
Tongue SCC
TUC338
HNSCC
HNSCC
ANRIL
CASC9
Cancer subtype
Gene
Table 1 (continued)
6
-
87 patients
23 patients, BALB/c nude mice
90 patients and 90 healthy subjects 23 paired cancer tissues and ANTs, athymic nude mice 65 LSCC tissues and paired ANTs; BALB/c nude mice
58 patients
32 tumor and 12 ANTs, 66 tumor and 56 ANTs
25 paired cancerous and ANTs
26 patients
Tissue samples of SCC tumors (n=6) and normal skin (n=7), Tissue microarrays consisting of samples from normal sunprotected skin (n=9), actinic keratosis (n=26), SCC in situ (n=20), and SCC (n=21); 53 patient tumors and paired ANTs
25 pairs of tumor and ANTs
-
Samples
-
Fadu, SCC-25, CAL-27, Tca8113, Hs 680.Tg CAL 27, SCC-9
CAL-27, SCC-9 and SCC-25
Cal27, NOK, JHU029 and JHU022 HEp-2 and SCC10A
UM -SCC 10A/ B, −11B, −14A/ B, −17A/ B, −47, −104, UT -SCC -14, −24A/ B, − 33, UD -SCC 1, − 2, − 3, − 5, − 6, −7A, − 8, FaDu, HaCaT, VM-CUB1, SW-1710, HT-1376, 5637, BFTC-905, HBLAK SCC4, SCC9, SCC1, SCC25, TU183, HSU3, FADU, OEC-M1, SNU1041, SCC15, NHOK AMC-HN-8
AMC-HN-8 and Hep-2
Cal-27 and Tca8113
TU-212, Hep-2 and NP-69
FaDu
NHEKs, cSCC cell lines
CAL-27 and SCC-9
FaDu, CAL27
Assessed cell line
CD63
-
microRNA-4301
miR-483-5p
Caspase 9, PARP, c-Myc, ASK1and AKT1 PTEN, EZH2
GSK-3β
miR-185-5p, Ki-67, CCND2, Cyclin D2
E-Cadherin, BCL2
β-Catenin, Claudin-1 and Vimentin -
CARM1, Sox-2
-
DUSP6, MMP13, Ki-67, p38α and p38δ
-
PI3K/Akt
-
-
SOX2-OT–EZH2–PTEN
c-Myc/AKT1/p38 MAPK
Wnt/β-catenin
miR-185-5p/CCND2
-
-
-
ST7-AS1/CARM1/Sox-2
-
ERK1/2, ERK/MAPK
-
-
β-catenin, CCND1, MYC, GSK3β, glycogen synthase kinase 3 beta ARF mRNA, p15 and p16 -
Signaling pathways
Gene interaction
-
Poor prognosis
Good prognosis
-
Poor prognosis
Poor prognosis
Poorer prognosis
Poor prognosis, neck nodal metastasis, and clinical stage Poor prognosis
Poor prognosis
Significantly worse prognosis Poor prognosis
-
-
-
Association with patient outcome
(Wang et al., 2019a) (Wang et al., 2016a)
(Tian et al., 2019)
(Sun et al., 2019) (Sur et al., 2019) (Tai et al., 2019)
(Sun et al., 2017)
(Sassenberg et al., 2019)
(Qiu et al., 2019) (Qu et al., 2018)
(Qian et al., 2017) (Tai et al., 2019)
(Matsunaga et al., 2019) (Ouyang et al., 2017) (Piipponen et al., 2016)
Ref.
(continued on next page)
Chemo resistance, apoptosis, cisplatin-induced PI3K activity, activation phosphorylation of Akt
Cell proliferation, invasion and migration Tumor growth, apoptosis, cell proliferation Cell proliferation, migration, invasion, cell apoptosis, tumor volume and tumor weight Mitochondrial fission, cisplatin sensitivity, apoptosis, growth Cell proliferation, Apoptosis
Cell proliferation
Cell proliferation, migration and invasion, chemo resistance
Cell proliferation, invasion, apoptosis, metastasis TNM stages, metastasis, migration, tumor sphere formation Cell Migration, Invasion and Proliferation, EMT, apoptosis Cell growth, migration, and invasion
Cell proliferation, regulation of G1 phase progression Cell proliferation and apoptosis Cell proliferation and migration
Functions
S. Ghafouri-Fard, et al.
Experimental and Molecular Pathology 112 (2020) 104353
31 OSCC tumor tissues and ANTs, BALB/c nude mice
-
Laryngeal SCC
HNSCC
Oral SCC
Oral SCC
Oral SCC
Tongue SCC
Oral SCC
Oral SCC
Laryngeal SCC
Oral SCC
Laryngeal SCC
HNSCC
HNSCC
Oral SCC
Oral SCC
Laryngeal SCC
HNSCC
Oral SCC
MIR31HG
(Wang et al., 2019b)11AS HOTAIR
lnc-p23154
AFAP1-AS1
HOTAIR
SNHG20
7
H19
HOTAIR
XIST
MYOSLID
HuR
LINC00662
FEZF1-AS1
RGMB-AS1
LINC00460
TUG1
42 pairs of OSCC tissues and ANTs 49 paired LSCC tissues and ANTs, nude mice 54 HNSCC tissues and their ANTs
34 Tumor tissues and ANTs; BALB/c mice 15 paired fresh cancer tissues and ANTs, 502 cases of HNSCC and 44 ANTs 73 pairs of HNSCC paraffinembedded tissue samples TSCC samples and ANTs
12 pairs of OSCC patients and matched ANTs; 4-week-old mice 5 matched samples of LSCC tissues and ANTs, 82 matched cancerous and ANTs, BALB/c mice 76 OSCC samples and ANTs
103 pairs of human TSCC tissues and corresponding ANTs, BALB/c athymic nude mice 50 tumor and ANTs
49 OSCC and ANTs, BALB/c nude mice
52 LSCC patients and 49 patients with polyps of vocal cords 52 Pairs of tumor tissues and ANTs; BALB/c mice 60 patients; Nude mice
NEAT1
Samples
Cancer subtype
Gene
Table 1 (continued)
PCI-13, FaDu, SCC-15, UMSCC-10A
Hs 680.Tg, Fadu, SCC-25, CAL27 and Tca8113 Hep-2 and AMC-HN-8
SCC25, HN4, Cal27, SCC4, HN30, HN12, HN13 and FaDu HIOEC, CGHNC9, ISG15, SCC9, and SCC25
Tca8113, HIOEC, Cal27, SCC4 and SCC9
Hep-2 and HEK293T
TSCCA, Tca8223, CAL-27, Tb3.1
Hep-2
HIOEC, Tca8113, UM-1 and CAL-27 SCC9, SCC15, SCC25, Ca9-22, HSU3, TSCCA, Fadu, NHOK
SCC-15, Tca8113, SCC-4, SCC9, CAL-27
UM1, HSC-4, HSC-6, NOK, HEK 293T, SCC-15, SCC-25, CAL-27
STC2, miRNA-206, AKT, ERK, Beclin 1, cleaved-PARP, Bax, cleaved- caspase 3 FMNL2, miR-219, FMNL2-WT
miR-22, NLRP3
miR-196a
HOTAIR, miR-7, bcl2l1, bcl3, birc3 and bcl2a1 Wnt3a and β-catenin
Slug, PDPN and LAMB3
EZH2, miR-124
EZH2, E-cadherin, PRC2 complexes
miR-148a-3p, DNMT1
ALDH1, LIN28, Nanog, Oct4, SOX2, miR-197
-
MAP1LC3B, Beclin1, ATG3, ATG7, N –cadherin, vimentin, E–cadherin, caspase 3, caspase 7, Mcl-1, survivin, bcl -2, MDR1 miR-378a-3p, HK2, PKM2, Glut1, LDHA, MMP1, CTGF, N –cadherin, vimentin, E–cadherin SLUG, SNAIL1, VIM, CADN, ZEB1, ZEB2, SMAD2, NANOG, NESTIN, SOX2, TWIST1
miR-214-3p, PIM1
NHOK, TSCCA, CAL-27, SCC-9, Tca8113 KB, CAL -27
s HIF1A, P21, CCND1
CDK6, miR-107
Gene interaction
Fadu, Cal-27
Hep-2
Assessed cell line
TUG1/miR-219/FMNL2
f LINC00460/ miR-206/ STC2, AKT signaling
RGMB-AS1/miR-22/NLRP3
-
Wnt/β-catenin
-
-
miR-124-3p/EZH2
-
H19/miR-148a-3p/DNMT1
SNHG20/miR-197/LIN28
-
Wnt/β-catenin
Glut1-mediated glycolysis
-
HOXA11-AS/miR214-3p/ PIM1
-
miR-107/CDK6
Signaling pathways
Poor prognosis
Shorter overall survival
Poor prognosis
Shorter overall survival Tumor size, stage and lymph node metastasis Poor prognosis
Poor prognosis
-
Poor prognosis
Poorer overall survival
-
Poorer prognosis
Poor prognosis
-
-
-
Poor prognosis
Lymph node metastasis and clinical stage -
Association with patient outcome
(Xu et al., 2019) (Xu and Xi, 2019) (Xue et al., 2019)
(Xu et al., 2016) (Xue et al., 2019)
(Xiao et al., 2019b) (Xiong et al., 2019)
(Wu et al., 2015)
(Xu et al., 2016)
(Wu and Xie, 2015) (Wu et al., 2019)
(Wang et al., 2018f)
(Wang et al., 2018e)
(Wang et al., 2018c)
(Wang et al., 2019b)
(Wang et al., 2016b) (Wang et al., 2018b)
(Wang et al., 2014)
Ref.
(continued on next page)
Cell viability, migration, invasion, metastasis Cell proliferation and migration, invasion, apoptosis Cell proliferation, clinical stage Tumor growth, cell proliferation and invasion Cell cycle, autophagy and apoptosis
Cell invasion proliferation, colony formation and metastasis Cell proliferation, migration, and invasion, tumor growth Cell invasion, migration and metastasis, EMT
Cell growth, cell cycle, and apoptosis Proliferative ability, mammosphere-forming ability, and tumor growth Cell migration, invasion and proliferation
Cell proliferation, invasion and survival, cell cycle arrest
Invasion-metastasis potential, tumor size, cell migration and invasion
Cell proliferation, migration, invasion, autophagy, apoptosis and sensitivity to cisplatin
Proliferation, apoptosis and cell cycle arrest Cell proliferation, cell cycle progression, and cell apoptosis Cell Proliferation, cisplatin resistance
Functions
S. Ghafouri-Fard, et al.
Experimental and Molecular Pathology 112 (2020) 104353
Cancer subtype
Tongue SCC
Laryngeal SCC
Oral SCC
Oral SCC
HNSCC
Tongue SCC
Tongue SCC
Laryngeal SCC
Oral SCC
Oral SCC
Oral SCC
Tongue SCC
HNSCC
Oral SCC
Gene
THOR
LOC554202
CASC9
FAL1
PVT1
LINC00673
LINC00152
FTH1P3
LEF1-AS1
LINC00668
FTH1P3
HOTTIP
ANRIL
PAPAS
Table 1 (continued)
8
49 Fresh HNSCC tissues and ANTs; 6-week-old athymic nude mice
86 TSCC tissues and 14 ANTs
70 patients
50 patients, nude mice
88 pairs of OSCC tumor tissues and ANTs, BALB/c-nu male mice
Set 1: 15 paired primary TSCC tissues and ANTs, Set 2: paraffin-embedded SCC tissue samples from 202 cases of patients Set1: 15 TSCC and 14 nontumor lingual mucous membrane biopsies, Set2: 182 paraffin-embedded TSCC and 46 non-tumor lingual mucous membrane tissue samples, GSE30784: 167 cancer tissues and 45 ANTs, GSE9844: 26 cancer tissues and 12 ANTs 40 Fresh LSCC tissues and ANTs
40 pairs of tumor samples and ANTs Cohort 1: 35 fresh OSCC tissue and matched ANTs, Cohort 2: 84 paraffin-embedded tissue sections, SPF BALB/c nu/nu nude mice 20 pairs of OSCC tissues and ANTs 83 SCCHN and their ANTs; Tu686, FaDu cell lines, Athymic nude mice
SCC090 and SCC25 OSCC
CAL-27, SCC-9, HN4, HN6 and HN30
SCC4, SCC9, SCC1, SCC25, TU183, HSU3, FADU, OEC-M1, SNU1041, SCC15, NHOK SCC4, SCC9, SCC1, SCC25, TU183, HSU3, FADU, OEC-M1, SNU1041, SCC15 and NHOK -
NHOK, SCC9, FADU, SCC25, SCC1, TU183, HSU3, OECM1, SNU1041, SCC4, and SCC15
Hep-2 and TU212
-
Tca8113 and Cal27
HOKs, SCC6, SCC9, SCC25, HN4, and HN6 Tu686, FaDu
HOMEC, SCC15 and CAL27
Hep2
Tca-8113 and Cal-27
HN4, HN6, SCC-25, CAL-27, NHOK
46 tumors and matched ANTs, NOD/SCID mice
55 tongue cancer and 31 ANTs; Athymic nude mice
Assessed cell line
Samples
TGF-β1
miR-125a-3p, ELK1, FGF1, GRB2, NF1, FGFR1 and FGFR2
-
miR-224-5p, fizzled 5
miR-297, ki-67
MST1/2, SAV1, LATS1/2, MOB, YAP, Ki67
Caspase-3
SNHG5, LINC00520, LINC00094, LINC00511, EPB41L4A-AS1, and LINC00341, H19
-
E-cadherin, Vimentin, βcatenin, p-GSK3β,
microRNA-761, CRKL
p-AKT, p-mTOR, P62, BCL-2, BAX and the LC3BII/LC3BI ratio
IGF2BP1, IGF2, CD44, KRAS, Cyclin D1, Cyclin E1, p21 and p27 miR-31, RhoA
Gene interaction
-
ANRIL/miR-125a-3p/ FGFR1/MAPK
-
FTH1P3/miR-224-5p/ fizzled 5
miR-297/ VEGFA
Hippo LEF1-AS1/LATS1/ YAP1
Poor prognosis, T stage, distant metastasis, clinical stage Poor prognosis
Poor prognosis
Poor prognosis
Poor prognosis
Poor prognosis
Poor prognosis
-
-
Poor prognosis
Poor prognosis
Poor prognosis
Poor prognosis
-
Poor clinical outcomes
Association with patient outcome
-
Wnt/β-catenin
microRNA-761/CRKL
AKT/mTOR
-
THOR/IGF2BP1/IGF2-MEKERK
Signaling pathways
(Zhang et al., 2018a)
(Zhang et al., 2015)
(Zhang, 2017b)
(Zhang, 2017a)
(Zhang et al., 2019a)
(Yuan et al., 2019a)
(Yu et al., 2017b)
(Yu et al., 2017a)
(Ye and Jiao, 2019) (Yu et al., 2018)
(Yang et al., 2018) (Yang et al., 2019b)
(Yang et al., 2019b)
(Yan et al., 2017)
Ref.
(continued on next page)
Cell invasion and migration
Cell cycle, proliferation, tumor growth
Cell proliferation and colony formation
Cell proliferation, migration and invasion, apoptosis, lymph node metastasis Cell survival, proliferation and migration, apoptosis, tumor growth and cell cycle arrest Cell proliferation, tumor growth
Tumor size, invasion of muscles, lymph node metastasis, and recurrence
Cell proliferation and invasion, cervical lymph node metastasis, EMT, stemness Cell invasion, metastasis, tumor size
Proliferative potential
Cell growth, cell cycle and cell invasion Apoptosis, autophagy, tumor size, regional lymph node metastasis, cell proliferation
Cell proliferation, migration, invasion, cell cycle arrest, tumor growth, metastasis Cell proliferation
Functions
S. Ghafouri-Fard, et al.
Experimental and Molecular Pathology 112 (2020) 104353
Cancer subtype
Tongue SCC
Laryngeal SCC
Hypopharyngeal SCC
Laryngeal SCC
Laryngeal SCC
Tongue SCC
Oral SCC
Tongue SCC
HNSCC
Tongue SCC
Gene
KCNQ1OT1
LINC00668
PEG10
HOTAIR
PVT1
MIAT
HAS2-AS1
CASC15
HOTAIR
UCA1
Table 1 (continued)
9
124 TSCC tissues and paired normal tissue
-
30 TSCC samples and ANTs
96 OSCC tissues and paired normal mucosa, Nude mice
30 LSCC and corresponding ANTs 116 TSCC patients
40 LSCC tissue samples and ANTs
56 patients
24 paired-specimens
68 patients with OSCC and 52 healthy volunteers 95 ANTs and 102 TSCC tissues; BALB/c nude mice
Samples
SCC9, SCC15, SCC25, Cal27, and Tca8113
SCC1, SCC4, Cal27, UM1, NOK16B, NHOK Tca8113, Tca8113P160, Tb3.1, Tscca, Hep-2
SCC-9 and CAL-27
NHBEC, TU686, TU177, and LSC-1 SCC-9
Hep-2, AMC-HN8
FaDu
TU177, TU212, TU686 and AMC-HN-8
CAL27 and SCC9
Assessed cell line
MICU1, Bcl-2, BAX, Caspase-3, Cleaved Caspase-3, Cytochrome c MAPK/Erk1/2, p-MAPK/Erk1/ 2, AKT1/2, and p-AKT1/2, bcatenin, TCF-4, cyclin D1
miR-33a-5p, ZEB1, cyclin D1
E-cadherin, vimentin, βcatenin, N-cadherin, and SNAI1 Ki-67, E-cadherin, vimentin, p65 KD, HF-1α and NF-κB
miR-519d-3p
EZH2
-
hsa-miR-197-3p, hsa-miR-761, hsa-miR-204- 5p, hsa-miR211-5p, hsa-miR-134-5p, cleaved PARP and cleaved caspase-3, -7, and -9 ABL2, RAB3B, ENAH and HMGA2
Gene interaction
WNT/b-catenin
Mitochondrial apoptotic pathway
-
-
Wnt/β-catenin
-
-
-
-
Ezrin/Fak/Src
Signaling pathways
Lymph node metastasis, apoptosis, TNM Stage
Poor prognosis
-
Poor prognosis, cervical lymph node metastasis -
-
-
-
-
Low overall survival rate Poor prognosis
Association with patient outcome
Proliferation
Hypoxia-induced invasiveness, lymph node metastasis Cell proliferation, cycle, and migration Mitochondria Related Apoptosis, Tumor Growth
Cell proliferation, migration and invasion, cervical lymph node metastasis Cell proliferation, invasion and metastasis, tumor size, tumor node metastasis Cell proliferation and cisplatinum resistance, lymphatic metastasis Cell proliferation and migration, apoptosis Cell invasion, EMT
Cell proliferation and cisplatin resistance
Functions
(Yang et al., 2016b)
(Zuo et al., 2018) (Kong et al., 2015)
(Zhu et al., 2017)
(Zheng et al., 2019) (Zhong et al., 2019)
(Zheng et al., 2017)
(Zhao et al., 2017b)
(Zhao et al., 2019)
(Zhang et al., 2019c) (Zhang et al., 2018b)
Ref.
S. Ghafouri-Fard, et al.
Experimental and Molecular Pathology 112 (2020) 104353
122 patients and 52 healthy controls
40 paired OSCC and ANTs
69 Paired tumor specimens and their ANTs, athymic BALB/c nude mice
40 paired OSCC and ANTs
Oral SCC
Oral SCC
Oral SCC
Oral SCC
CASC2
10
HNSCC
Laryngeal SCC
Oral SCC
Oral SCC
lnc-IL17RA-11
PTCSC3
SOX21-AS1
GAS5
Oral SCC
Laryngeal SCC
Oral SCC
AC026166.2-001
45 Fresh OSCC tissues and normal control tissues
Oral SCC Oral SCC
LOC441178 MEG3
Oral SCC
BALB/c nude mice
Oral SCC Oral SCC
MORT LINC01133
C5orf66-AS1
Tumor tissue and ANTs from 59 patients 50 pairs of tissue samples with paired ANTs 52 patients 83 tumor samples and ANTs
Tongue SCC
FALEC
66 LSCC patients and 52 healthy volunteers Paired tumors and ANTs from 2 OSCC patients -
-
BALB/c nude mice
30 paired OSCC and ANTs
96 paraffin-embedded TSCC samples and 10 paired TSCC and matched ANTs; NOD/SCID mice 17 pairs of fresh TSCC tissues and ANTs; 8week-old male mice
Tongue SCC
NKILA
350 patient and 44 controls
Oral SCC
AC012456.4
Cancer samples and ANTs from 62 patients
Laryngeal SCC
NEF
Samples
Cancer subtype
Gene
HSC3, HSC6, SCC15, SCC25, cal-27, UM1
SAS, CAL27
SCC-47, SCC-104, SAS UM-SCC-17A
AMC-HN-8, TU-212
HIOEC, SCC25, CAL27, HB, Tca8113 SCC 9, HOK
H157 and HSC-2, and HEK-293
SCC-9, CAL-27, SCC25, SCC-4, SCC-6, SCC-15 SCC090, SCC25 NOK, CAL2, HN4, and 293FT SCC-25 SCC15 and Cal27
CAL27 Tca8113
Tca8113, TSCCA, CAL-27, SCC-9, HOK Tca8113, SCC-9, TSCCa, CAL-27, NOK Tca8113, TSCCA, CAL-27, SCC-9, NHOK -
SCC090, SCC25
UM-SCC-17A
Assessed cell line
E-cadherin, fibronectin, cyclin D1 miR-21, PTEN, Akt, E-cadherin, PCNA, cyclinD1, Ki-67, Ncadherin, vimentin, snail1
HOTAIR, STAT3
ER-α, CDK2, CCNA2, PCNA
CYC1, Bcl-2, Bax, cleaved Caspase-3/7/9, MMP9 miR-24-3p, p27 and cyclin D1
miR-21
miR-548d-3p, SOCS5, SOCS6
ROCK1, HIF-1α β-catenin, TCF-4 and cyclin D1
ROCK1 GDF15, MMP10, and MMP13
NF-κB, IκBα, Bay-117082, JSH23, E-cadherin, N-cadherin and vimentin, p65 EZH2, ECM1
-
CDK1
microRNA-21, PDCD4, Bax, Bcl2
CDK1
miRNA-21
-
Gene interaction
Table 2 Function of down-regulated lncRNAs in HNSCC (ANT: adjacent normal tissue, EMT: epithelial-mesenchymal transition).
miR-21/PTEN
-
-
P53
miR-24-3p/p27
-
miR-548d-3p/ JAK-STAT miR-548d-3p/ SOCS5/SOCS6 -
RhoA/ROCK WNT/β-catenin
-
-
CALCIUM, MAPK, JAK/ STAT NF-κB/Twist
-
CASC2/miR-21/ PDCD4
-
-
Wnt/β-catenin
Signaling pathways
-
Poor prognosis
-
disease prognosis
Poor prognosis
-
Poor prognosis
-
Poor prognosis -
Poor prognosis -
Good prognosis
Poor prognosis
Poor prognosis
-
-
-
-
Poor prognosis
Association with patient outcome
(Song et al., 2019) (Xiao et al., 2019a) (Yang et al., 2016a) (Zeng et al., 2019)
(Shen et al., 2018)
(Lu et al., 2018)
(Zhang et al., 2018a)
(Jin et al., 2019) (Kong et al., 2018) (Xu et al., 2018) (Liu et al., 2017b) (Tan et al., 2019)
(Jia et al., 2019)
(Huang et al., 2016)
(Wang et al., 2018d)
(Xing et al., 2019)
(Cui et al., 2019b) (Dong and Wu, 2019) (Xing et al., 2019) (Piipponen et al., 2016)
Ref
(continued on next page)
Cell growth and invasion, tumor size Cell proliferation, migration, invasion, and EMT
Cell proliferation, invasion, migration, growth, metastasis Cell proliferation, migration, clone-forming capacity, apoptosis DNA replication, cell cycle, base excision repair cell proliferation
Cell cycle, proliferation, migration
Cell proliferation cell migration and invasion, metastasis Cell invasion and migration Cell Proliferation, apoptosis, metastasis Cell migration, apoptosis
Cell migration and invasion, EMT, tumor size, lymph node metastasis Cell proliferation, migration, colony formation, metastasis
Regulation of cell activation
Cell growth, migration and invasion
Cell growth, migration and invasion Cell proliferation, apoptosis, lymph node metastasis
Cell proliferation, Tumor size
Cell proliferation, Apoptosis
Functions
S. Ghafouri-Fard, et al.
Experimental and Molecular Pathology 112 (2020) 104353
Experimental and Molecular Pathology 112 (2020) 104353
Ref
(Zhao et al., 2017a) (Zhou et al., 2016) Cell proliferation, migration and invasion, apoptosis, EMT Cell proliferation, invasion, growth, metastasis, apoptosis Poor prognosis
Poor prognosis
Signaling pathways
AKT
-
Gene interaction
CDH1, miR-205-5p, E-cadherin, Snail2 and vimentin SNU899 and SNU46
FaDu
51 patients
global profiling: 3 paired primary cancerous and ANTs, confirmation: 20 HSCC specimens and ANTs, 138 HSCC patients
Cancer subtype
Laryngeal SCC
Hypopharyngeal SCC
Gene
RP11-169D4.1
AB209630
Table 2 (continued)
Samples
Assessed cell line
Association with patient outcome
Functions
S. Ghafouri-Fard, et al.
identified 728 lncRNAs with differential expression between these two sets of samples. Notably, expression patterns of 55 lncRNAs were associated with survival of patients (Nohata et al., 2016). Through analyzing RNA-sequencing data of 422 HNSCC patients, Zou et al. have identified 276 intergenic lncRNAs whose expression profile predicted overall patients' survival (Zou et al., 2016). 5. Diagnostic value of lncRNAs in HNSCC Dysregulation of expression of lncRNAs in HNSCC tissues and peripheral blood potentiates them as diagnostic biomarkers in this type of cancer. Yao et al. have assessed overall lncRNA signature in both tumoral and peripheral blood samples of HNSCC patients using microarray and RNA-seq methods. They demonstrated differential expression of 432 lncRNAs in peripheral blood samples and 333 lncRNAs in tissues samples. Among these lncRNAs, HOXA11-AS, LINC00964 and MALAT1 showed significant up-regulation in the plasma of HNSCC patients compared with in healthy subjects with combined areas under the curve values of 0.925 and 0.839 in training and validation sets, respectively. So, their study suggested these three lncRNAs as putative diagnostic markers for HNSCC (Yao et al., 2018). Notably, only 12 lncRNAs were common between tumoral tissues and plasma samples (Yao et al., 2018). This finding is in accordance with a previous study which showed expression of HOTAIR, HULC, MALAT1, MEG-3, NEAT-1 and UCA1 in tissues from patients with oral SCC, but only two of these lncRNAs were detectable in saliva samples (Tang et al., 2013). 6. Putative therapeutic implications Animal studies have verified the role of several lncRNAs in the pathogenesis of HNSCC. Knock-down experiments have also shown decreased tumorigenic potential of cancer cell lines after silencing certain lncRNAs. For instance, Wang et al. have made a subcutaneously implanted tumor model in the nude mice after silencing MIR31HG in SCC cells. They reported decreased tumor volume and weight in the lncRNA-silenced group compared with controls (Wang et al., 2018b). Other knock-down assays verified potential use of siRNA-mediated lncRNA silencing in animal models. Experiments in a murine model of metastasis have shown the effects of MALAT1 knock down in decreasing number and size of tumor nodules. Moreover, suppression of MALAT1 using antisense oligonucleotides led to a significant decrease in metastasis (Sun and Ma, 2019). On the other hand, forced over-expression of tumor suppressor lncRNAs have resulted in decreased malignant behavior of implanted cancer cells in animal models (Ma et al., 2019). However, such experiments have not been validated in clinical settings. 7. Discussion Recent methods of lncRNA profiling have easily detected expression of lncRNAs in body fluids and tissues using simple molecular methods (Zhan et al., 2018; Yan et al., 2017). Such advances facilitate application of lncRNAs as biomarkers for early diagnosis of HNSCC or followup of patients after surgical removal of tumoral tissues or chemoradiation. Mechanistically, lncRNAs influence important signaling pathways and cellular processes such as cell proliferation, apoptosis and cell cycle progression. In addition to these processes, certain lncRNAs such as lnc-IL17RA-11 contribute in DNA repair mechanisms (Song et al., 2019). Many of dysregulated lncRNAs in HNSCC are among those with acknowledged roles in other types of cancers. Although this finding further approves their contribution in tumorigenesis, it complicates design of specific diagnostic panels for HNSCC. The most probable mechanism of lncRNA function in carcinogenesis is ceRNA role. A recent study has assessed lncRNA–mRNA interactions according to shared miRNAs between lncRNA–miRNA intersections and miRNA–mRNA interactions. Based on their results, ‘Chemokine signaling pathway’, ‘Focal adhesion’, ‘MAPK signaling pathway’, and 11
Experimental and Molecular Pathology 112 (2020) 104353
S. Ghafouri-Fard, et al.
‘Regulation of actin cytoskeleton’ have been among pathways controlled by competitive lncRNAs in oral SCC (Yang et al., 2019c). Such interactions with critical pathways in carcinogenesis potentiate lncRNAs as appropriate therapeutic targets for HNSCC. Based on the fundamental role of HPV in the carcinogenesis process of HNSCC, it is expected that oncoproteins of this virus represent targets of lncRNAs. However, only few studies have addressed association between lncRNAs profile and HPV load/ positivity. So, a future perspective of this research area is clarification of the functional interaction between lncRNAs and viral oncoproteins. The diagnostic power of lncRNAs in HNSCC has been assessed in few studies. The most promising results have been emerged for combination of HOXA11-AS, LINC00964 and MALAT1. Inclusion of other lncRNAs in such panels might increase sensitivity and specificity of these panels and suitability for diagnosis in a wider range of patients. Future studies are needed for this purpose. It is worth mentioning that SCC tumors from different anatomical sites might have distinct expression patterns of lncRNAs (Zou et al., 2015). Such finding complicates design of diagnostic panels and development of targeted therapeutic options. Meanwhile, it necessitates personalized approaches for both mentioned fields. Another forthcoming area of research is contribution of lncRNAs in determination of response of HNSCC patients to therapeutic options. MPRL, UCA1, KCNQ1OT1, HOTAIR and HOXA11-AS have been among lncRNAs whose expression levels might determine response of patients to cisplatin (Zhang et al., 2018b; Fang et al., 2017; Tian et al., 2019; Wang et al., 2019b; Wang et al., 2018c). However, based on the role of lncRNAs in the determination of several aspects of cancer cells fate, this list is expected to include several other lncRNAs as well. Differential expression of lncRNAs between radioresistant and parental nasopharyngeal carcinoma cell lines also implies contribution of these transcripts in conferring radioresistance (Zou et al., 2016). Consistent with the proposed role of lncRNAs in determination of response to therapies, cell line studies have shown alteration of lncRNA expression after irradiation or chemoexposure (Guglas et al., 2018). Taken together, lncRNAs are involved in the regulation of expression of several molecules and signaling pathways which participate in HNSCC. This kind of involvement potentiates them as biomarkers and therapeutic targets. This field is evolving, so it is expected that future therapeutic options would be designed to target lncRNAs-associated pathways.
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Declaration of Competing Interest The authors declare they have nothing to report. Acknowledgment This study was financially supported by Shahid Beheshti University of Medical Sciences. References Arunkumar, G., Deva Magendhra Rao, A.K., Manikandan, M., Arun, K., Vinothkumar, V., Revathidevi, S., Rajkumar, K.S., Rajaraman, R., Munirajan, A.K., 2017a. Expression profiling of long non-coding RNA identifies linc-RoR as a prognostic biomarker in oral cancer. Tumour Biol. 39 1010428317698366. Arunkumar, G., Murugan, A.K., Prasanna Srinivasa Rao, H., Subbiah, S., Rajaraman, R., Munirajan, A.K., 2017b. Long non-coding RNA CCAT1 is overexpressed in oral squamous cell carcinomas and predicts poor prognosis. Biomed. Rep. 6, 455–462. Chang, S.M., Hu, W.W., 2017. Long non-coding RNA MALAT1 promotes oral squamous cell carcinoma development via microRNA-125b/STAT3 axis. In: J Cell Physiol. Chen, F., Qi, S., Zhang, X., Wu, J., Yang, X., Wang, R., 2019a. lncRNA PLAC2 activated by H3K27 acetylation promotes cell proliferation and invasion via the activation of Wnt/ betacatenin pathway in oral squamous cell carcinoma. Int. J. Oncol. 54, 1183–1194. Chen, Y., Guo, Y., Yan, W., 2019b. lncRNA RP5-916L7.2 correlates with advanced tumor stage, and promotes cells proliferation while inhibits cells apoptosis through targeting miR-328 and miR-939 in tongue squamous cell carcinoma. Clin. Biochem. 67, 24–32.
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Upregulated long non-coding RNA LINC00152 expression is associated with progression and poor prognosis of tongue squamous cell carcinoma. J. Cancer 8, 523–530. Yu, C., Wang, Y., Li, G., She, L., Zhang, D., Chen, X., Zhang, X., Qin, Z., Cao, H., Liu, Y., 2018. LncRNA PVT1 promotes malignant progression in squamous cell carcinoma of the head and neck. J. Cancer 9, 3593–3602. Yuan, H., Jiang, H., Wang, Y., Dong, Y., 2019a. Increased expression of lncRNA FTH1P3 predicts a poor prognosis and promotes aggressive phenotypes of laryngeal squamous cell carcinoma. Biosci. Rep. 39. Yuan, J., Xu, X.J., Lin, Y., Chen, Q.Y., Sun, W.J., Tang, L., Liang, Q.X., 2019b. LncRNA MALAT1 expression inhibition suppresses tongue squamous cell carcinoma proliferation, migration and invasion by inactivating PI3K/Akt pathway and downregulating MMP-9 expression. Eur. Rev. Med. Pharmacol. Sci. 23, 198–206. Zeng, B., Li, Y., Jiang, F., Wei, C., Chen, G., Zhang, W., Zhao, W., Yu, D., 2019. LncRNA GAS5 suppresses proliferation, migration, invasion, and epithelial-mesenchymal transition in oral squamous cell carcinoma by regulating the miR-21/PTEN axis. Exp. Cell Res. 374, 365–373. Zhan, Y., Du, L., Wang, L., Jiang, X., Zhang, S., Li, J., Yan, K., Duan, W., Zhao, Y., Wang, L., Wang, Y., Wang, C., 2018. Expression signatures of exosomal long non-coding RNAs in urine serve as novel non-invasive biomarkers for diagnosis and recurrence prediction of bladder cancer. Mol. Cancer 17, 142. Zhang, C.Z., 2017a. Long intergenic non-coding RNA 668 regulates VEGFA signaling through inhibition of miR-297 in oral squamous cell carcinoma. Biochem. Biophys. Res. Commun. 489, 404–412. Zhang, C.Z., 2017b. Long non-coding RNA FTH1P3 facilitates oral squamous cell carcinoma progression by acting as a molecular sponge of miR-224-5p to modulate fizzled 5 expression. Gene 607, 47–55. Zhang, H., Zhao, L., Wang, Y.X., Xi, M., Liu, S.L., Luo, L.L., 2015. Long non-coding RNA HOTTIP is correlated with progression and prognosis in tongue squamous cell carcinoma. Tumour Biol. 36, 8805–8809. Zhang, T.H., Liang, L.Z., Liu, X.L., Wu, J.N., Su, K., Chen, J.Y., Zheng, Q.Y., Huang, H.Z., Liao, G.Q., 2017. Long non-coding RNA MALAT1 interacts with miR-124 and modulates tongue cancer growth by targeting JAG1. Oncol. Rep. 37, 2087–2094. Zhang, L.L., Hu, D., Zou, L.H., 2018a. Low expression of lncRNA MEG3 promotes the progression of oral squamous cell carcinoma by targeting miR-21. Eur. Rev. Med. Pharmacol. Sci. 22, 8315–8323. Zhang, S., Ma, H., Zhang, D., Xie, S., Wang, W., Li, Q., Lin, Z., Wang, Y., 2018b. LncRNA KCNQ1OT1 regulates proliferation and cisplatin resistance in tongue cancer via miR211-5p mediated Ezrin/Fak/Src signaling. Cell Death Dis. 9, 742. Zhang, C., Bao, C., Zhang, X., Lin, X., Pan, D., Chen, Y., 2019a. Knockdown of lncRNA LEF1-AS1 inhibited the progression of oral squamous cell carcinoma (OSCC) via Hippo signaling pathway. 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Experimental and Molecular Pathology journal homepage: www.elsevier.com/locate/yexmp
Review
Expression and function of long non-coding RNAs in head and neck squamous cell carcinoma Soudeh Ghafouri-Farda, Hossein Mohammad-Rahimib, Marzieh Jazaeric, Mohammad Taherid,
T ⁎
a
Department of Medical Genetics, Shahid Beheshti University of Medical Sciences, Tehran, Iran School of Dentistry, Shahid Beheshti University of Medical Sciences, Tehran, Iran c School of Dentistry, Hamadan University of Medical Sciences, Hamadan, Iran d Urogenital Stem Cell Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran b
ARTICLE INFO
ABSTRACT
Keywords: Long non-coding RNA Head and neck squamous cell carcinoma
No longer regarded as junk DNA, long non-coding RNAs (lncRNAs) are considered as master regulators of cancer development and metastasis nowadays. Among the recently appreciated roles of these transcripts is their fundamental contribution in the pathogenesis of head and neck squamous cell carcinoma (HNSCC). Notably, lncRNAs may have interactions with some environmental risk factors for this type of cancer. Moreover, a number of studies have verified diagnostic and prognostic values of lncRNAs in HNSCC. Emerging evidences from functional studies point to the possibility of design of lncRNA-targeted therapies in HNSCC. In the current review, we discuss the molecular mechanisms for participation of lncRNAs in the pathogenesis of HNSCC, their potential application in cancer diagnosis and most importantly in the development of personalized methods for treatment of HNSCC.
1. Introduction Head and neck squamous cell carcinoma (HNSCC) has an annual rate of 500,000 new cases worldwide (Torre et al., 2015). This type of cancer originates from various anatomic sites including oral cavity, oropharynx, hypopharynx, larynx, nasopharynx, palatine, and lingual tonsils (Marur and Forastiere, 2016a). HNSCC has been associated with some environmental/ life style risk factors including tobacco smoking, alcohol use, and viral infections (Marur and Forastiere, 2008; Sturgis and Cinciripini, 2007). Notably, human papillomavirus (HPV) is regarded as a risk factor for development of oropharyngeal cancer (Sturgis and Cinciripini, 2007). Surgery or radiotherapy, combination of surgery with adjuvant radiation or chemoradiation, and chemotherapy with or without a biological drug are recommended for early stage, locally advanced and metastatic disease, respectively (Marur and Forastiere, 2016b). Based on such trend in the complexity of treatment modalities as the disease progresses, early detection of HNSCC has clinical importance. For such purpose, identification of molecular pathways which are involved in each step of cancer progression is a critical necessity. Recent studies have highlighted the role of a group of transcripts namely long non-coding RNAs (lncRNAs) in the pathogenesis of diverse cancers including HNSCC (Guglas et al., 2017). This group of transcripts has no obvious open reading frame to produce
⁎
functional proteins, yet regulating gene expression at several levels and are implicated in the evolution and progression of human cancers (Sanchez Calle et al., 2018). A well-known mechanism for their involvement in the pathogenesis of cancer is their function as miRNAs sponges to decline effects of miRNAs on the mRNAs (Deng et al., 2015). LncRNAs participating in the carcinogenesis process were mainly associated with cellular macromolecules such as chromatin, protein and other types of RNA molecules (Huarte, 2015; Zhang et al., 2019b). Fig. 1 depicts a summary of cellular pathways influenced by lncRNAs in HNSCC. In the present review, we summarize recent findings regarding the role of lncRNAs in the pathogenesis of HNSCC. 2. Expression of lncRNAs in HNSCC LncRNAs can be classified to oncogenic and tumor suppressor transcripts based on their expression pattern in tumoral tissues versus non-tumoral tissues of the same origin and functions in regulation of cell cycle, apoptosis and cell proliferation. Several studies have shown up-regulation of numerous lncRNAs in cell lines or patients’ sample of HNSCC origin. Table 1 summarizes the information about these upregulated lncRNAs which are putative oncogenic lncRNAs. The mostly assessed lncRNA in HNSCC is MALAT1. Several studies have reported
Corresponding author. E-mail address: [email protected] (M. Taheri).
https://doi.org/10.1016/j.yexmp.2019.104353 Received 12 October 2019; Received in revised form 25 November 2019; Accepted 4 December 2019 Available online 05 December 2019 0014-4800/ © 2019 Elsevier Inc. All rights reserved.
Experimental and Molecular Pathology 112 (2020) 104353
S. Ghafouri-Fard, et al.
Fig. 1. (A) GAS5 acts as a tumor suppressor in Oral SCC. This lncRNA exerts its function through suppression of miR-21 and subsequent up-regulation of PTEN (Zeng et al., 2019). Reduced level of GAS5 leads to increased levels of miR-21 and inhibition of PTEN. (B) LncRNA PTCSC3 suppresses cell proliferation in laryngeal SCC through down-regulation of lncRNA HOTAIR. This effect is probably exerted through down-regulation of STAT3 (Xiao et al., 2019a). (C) Overexpression of the lncRNA MORT suppresses oral SCC cell proliferation by down-regulating ROCK1 (Jin et al., 2019). (D) NKILA suppresses the epithelial-mesenchymal transition (EMT) process through obstruction of the phosphorylation of IκBα and NF-κB induction (Huang et al., 2016).
up-regulation of this lncRNA in oral SCC samples and verified its role in enhancement of cell proliferation, anchorage-independent growth and migration as well as inhibition of apoptosis. Higher levels of this lncRNA have been associated with lymph node metastasis and poor survival of cancer patients (Han et al., 2019; Fang et al., 2016). Consistent with the acknowledged competing endogenous (ce) RNA role for lncRNAs, functional assays have identified several lncRNA-miRNA pairs whose interactions alter the carcinogenesis process. Besides, aberrant expression of lncRNAs has been associated with dysregulation of Wnt/ β-catenin, PI3K/Akt and NF-κB signaling pathways in cancerous tissues. A number of lncRNAs have been shown to be down-regulated in HNSCC samples and cell lines compared with non-cancerous cells (Table 2). Generally, down-regulation of these lncRNAs has been associated with poor survival of cancer patients. These lncRNAs are also involved in the regulation of cell cycle progression, cell proliferation and apoptosis. Among the most evaluated tumor suppressor lncRNAs are CASC2 and MEG3. A recent study has shown down-regulation of CASC2 in oral SCC samples in association with adverse clinicopathological features. Functional studies have shown that forced overexpression of this lncRNA suppresses cell proliferation partially via enhancement of cell apoptosis and induction of cell cycle arrest. Notably, CASC2 is regarded as a ceRNA for miR-21 to stimulate expression of PDCD4. Tumor suppressor role of this lncRNA has been verified in vivo as well (Pan et al., 2019). MEG3 is another tumor suppressor lncRNA that suppresses cell proliferation, migration and invasion of SCC cells. Function of this lncRNA is exerted at least partly through
sponging miR-4261. The role of MEG3 in suppression of tumor growth has been also verified in animal models (Ma et al., 2019). 3. Correlations between lncRNAs and viral infections in HNSCC Nohata et al. have identified 140 lncRNAs with differential expression between HPV positive tumors and HPV negative ones (Nohata et al., 2016). Ma et al. have shown higher numbers of myeloid-derived suppressor cells (MDSCs) in HPV-positive HNSCC compared with normal controls. Moreover, they have reported 132 distinct lncRNAs in diverse HPV infected states of HNSCC. Notably, HOTAIR, PROM1, CCAT1, and MUC19 levels have been inversely correlated with aggregation of MDSCs in HPV-associated HNSCC (Ma et al., 2017a). 4. Prognostic value of lncRNAs in HNSCC Recently, Yang et al. have proposed a panel of lncRNAs which could predict survival prognosis of HNSCC patients through assessment of RNA-seq data of 269 patients. This panel included AC010624.1, AC130456.4, LINC00608, LINC01300, MIR99AHG, AC008655.1, AC055758.2, and AC118553.1 (Yang et al., 2019a). Another study has evaluated lncRNA expression data in 425 HNSCC patients and reported that three lncRNAs (AC002066.1, AC013652.1 and AC016629.3) were significantly associated with survival in an independent manner from clinical features (Wang et al., 2018a). Nohata et al. have assessed RNAseq data of 426 HNSCC and 42 adjacent normal tissues and have 2
3
Laryngeal SCC
Oral SCC
Tongue SCC
Oral SCC
MIR155HG
CRNDE
LINC00511
FLJ22447
54 OSCC tumor samples; SPF grade Nu/Nu nude mice
72 tumor tissues and ANTs
Human HNSCC Specimens, 4week-old BALB/c-nu mice
30 paired cancer specimens and ANTs
Tongue SCC
HNSCC
Tongue SCC
32 TSCC and paired ANTs
SCC specimens from 52 patients and normal oral mucosa tissue specimens from 25 healthy individuals, BALB/ c-nu mice SCC tissues and corresponding ANTs from 20 patients 10 paired ANTs and tumor tissues; BALB/c-nu/nu T celldeficient mice 41 HNSCC samples from different anatomical sites and peripheral blood sample 94 TSCC tissue specimens and matched ANTs 127 TSCC samples, ANTs and lymph node metastases (if exist), Six-week-old male nude mice 14 OSCC and ANT pairs
30 tumor tissues and paired ANTs 58 patients, 30 specific pathogen free male BALB/c nude mice Tumor samples and ANTs from 45 patients
60 oral SCC specimens and 8 ANTs 60 oral cancer and 8 normal tissue samples OSCC tissues samples and ANTs from 48 patients
Samples
Oral SCC
Oral SCC
Tongue SCC
Tongue SCC
Tongue SCC
Oral SCC
LINC01116
MALAT-1
Tongue SCC
RP5-916L7.2
Tongue SCC
Oral SCC
PLAC2
UCA1
Oral SCC
CCAT1
HNSCC
Oral SCC
Linc-RoR
H19
Cancer subtype
Gene
CAL-27, SCC-9, SCC-4, SCC-15 and SCC-25
SCC15, SCC25, CAL27, HaCaT
SCC4, SCC15, SCC25, Hs 680.Tg
Tca8113, SCC-25, CAL-27, HN5, Hs680.Tg Tscca, Tca8113P160, Tca8113 and Hep-2
SCC-9 and CAL-27
STAT3, miR-30a, E-cadherin, N-cadherin, vimentin, Twist and MMP2/9 miR-124, JAG1
Ki67, MMP2/9, N-cadherin, Vimentin, E-cadherin, βcatenin, NF-κB MMP-9, Akt (phosphorylation), MEG3
miR-125b, STAT3
BAX, vimentin, E-cadherin, DKK1
SPRR1B, SPRR2A, SPRR2E, LAYN, CCT4, CTHRC1, and FHL1
CAL27 and SCC-25
SSC4
MALAT-1, MEG3
IGF2, CCCTC-binding factor, p57KIP2
IL-33
miR-765, LAMC2
E-cadherin, p-GSK-3β, βcatenin, N-cadheri, vimentin and Snail protein
miR-155-5p
miR-136
miR-328-5p and miR-939-5p
p53, c-Myc, Klf4, Oct4, Sox2, miR-145-5p c-Myc, miR155-5, let7b-5p, miR218-5, miR490-3p H3K27ac
Gene interaction
Tca8113
-
HOEC cells, Tca-8113, SCC-9, SCC-4 and CAL-27 HSC-3
Immortalized HOK cells, Tca8113, SCC-9, TSCCA, CAL27 and SCC-15
TU686, TU177, AMC-HN-8, 293T cells
SciL-0682, Tca83, TSCC, NB, NT
Tca-8113
SCC-9, CAL-27
-
Assessed cell line
Table 1 Function of up-regulated lncRNAs in HNSCC (ANT: adjacent normal tissue, EMT: epithelial-mesenchymal transition).
MALAT1/miR-124/JAG1
STAT3/malat1/miR-30a
PI3K/Akt
β-catenin and NF-κB
MALAT1/miR-125b/STAT3
Wnt/b-catenin
-
-
-
-
LINC00511/miR-765/ LAMC2 LncRNA-CAF/IL-33
Wnt/β-catenin
miR-155-5p/SOX10
LINC01116/miR-136/FN1
-
Wnt/β-catenin
P53 signal pathway
Signaling pathways
-
Poor Prognosis
Poorer overall survival
Poor prognosis
-
-
-
Lymph node metastasis -
Tumor recurrence
Poor prognosis
-
Poor prognosis, lymph node metastasis Poor prognosis
Poor prognosis
Poor prognosis, tumor size, TNM stage -
Poor prognosis
-
Association with patient outcome
(Zhang et al., 2017)
(Wang et al., 2018d)
(Yuan et al., 2019b)
(Chang and Hu, 2017) (Zhou et al., 2015)
(Liang et al., 2017a)
(Han et al., 2019)
(Fang et al., 2014) (Fang et al., 2016)
(Esteves et al., 2005)
(Ding et al., 2018a) (Ding et al., 2018b)
(Dai et al., 2019)
(Cui et al., 2019a)
(Chen et al., 2019b) (Chen et al., 2019c)
(Arunkumar et al., 2017a) (Arunkumar et al., 2017b) (Chen et al., 2019a)
Ref.
(continued on next page)
Cell proliferation, apoptosis, anchorage-independent growth, migration Lymph node metastasis, cell migration, invasion, EMT, apoptosis Metastasis, Cell proliferation, Apoptosis Tumor growth and metastasis, cell migration and invasion, EMT Cell proliferation, migration and invasion, distant metastasis EMT, metastasis, HNSCC outgrowth, proliferative capacity, tumor size Cell growth, proliferation, invasion, metastasis
Metastasis
Cell migration
Cell proliferation, Cell cycle distribution and invasion Cell proliferation, Migration and therapy-induced apoptosis
Cell proliferation, Migration, Invasion, EMT and apoptosis
Cell proliferation, migration, invasion
Cell proliferation, invasion and migration
Cells proliferation, Apoptosis
Cell cycle transition, Cell proliferation, Cell migration Cell proliferation, Migration, Invasion,
Cell proliferation, metastasis
Functions
S. Ghafouri-Fard, et al.
Experimental and Molecular Pathology 112 (2020) 104353
4
Oral SCC
HNSCC
nasopharyngeal carcinoma Oral SCC
Oral SCC
HNSCC
Laryngeal SCC
-
HNSCC
Oral SCC
Oral SCC
Tongue SCC
Laryngeal SCC
CEBPA-AS1
LINC00473
LncRNA-ROR
NEAT1
LINC00958
MIR100HG
CCAT1
ZFAS1
FOXCUT
LUCAT1
H19
HOTAIR
WWTR1-AS1
HNSCC
HNSCC
HNSCC
H19
H1
Laryngeal SCC
SNHG1
72 patients; Hep-2 cell line, BALB/c mice Athymic female nude mice
50 Paired OSCC tissues and ANTs 16 patients
23 OSCC tissue specimens with matched ANTs
NOD-SCID Gamma (NSG) mice
70 tumor and ANTs
42 freshly frozen OSCC tissues, as well as 42 matched controls, BALB/c nude mice 30 OSCC tissues and their ANTs; Ten female athymic BALB/c nude mice 48 cases of paired HNSCC and ANTs
78 paired of clinical HNSCC and matched ANTs BALB/c nude mice
60 pairs of OSCC tissues and matched ANTs
62 HNSCC samples and ANTs from 19 samples
65 matched cancerous and ANTs
40 TSCC tissues and ANTs; Nu/ Nu nude mice 30 OSCC tumor tissues and ANTs, BALB/c nude mice
Tongue SCC
Oral SCC
Samples
Cancer subtype
UCA1
Gene
Table 1 (continued)
Tu686, TSCCA and Cal27, Tb3.1, HIOEC
Tca8113, OSC-4, SCC1, SCC2, SCC4, SCC9, CAL-27, UM1, UM2, SMMC7721, HCCLM3, HUH7, HEPG2, MCF7, BT474, SKBR3, HCC1187, HCC1143, LO2, HOK, MCF-10A Tca8113, TSCCA, CAL-27, SCC-9, NHOK CAL27, SCC9, SCC15, SCC25, and FaDu Hep-2
DOK, SCC-040, SCC-25, FaDu
KYSE, TE-5 and TT, UMSCC1, 93UV147, SK-MES-1, Calu-1, ChagoK1, H520, H2170, H226
HOK, HEK-293T, Detroit 562, Cal27, SCC-9, SCC-15, and Fadu UM-SCC-17A,
hNOK, SCC-9, SCC-25, HN4, Tca-8113 and Cal-27
SCC9, SCC15, SCC25, and CAL2, OKC NP69, CNE-1, CNE-2, HONE-1, HNE-1 SCC-4, SCC-15, CAL-27, HSC-3, HSC-2, Ca9-22, HOK-16B
STC2, miR-206
miR-let-7, HMGA2, vimentin, N-cadherin, twist, zeb1, snail1 PTEN
PI3K/AKT, HOTAIR/miR206/STC2 WWTR1-AS1/WWTR1
-
H19/let-7a/HMGA2
-
FOXC1/FOXCUT
FOXC1, MMP2, MMP7, MMP9, VEGF-A
PCNA
Cadherin, integrin, EGFR, FAS, FGF, insulin/IGF, TGFβ, VEGF, interleukin, JAK/ STAT, PDGF, PI3K, p53, p38, Ras, Toll receptor, Wnt
TP63/SOX2-CCAT1-EGFR, MEK/ERK1/2, PI3K/AKT
MIR100HG/ miR-204-5p
LINC00958/c-Myc
NEAT1/miR-365/RGS20
H19/miR-138/EZH2
LncRNA-ROR/P53
Wnt/β-catenin
CEBPA-AS1/CEBPA/Bcl2
H19/miR-675
miR-375/YAP1/Hippo
UCA1/miR-184
miR-140-5p/PAK1
Signaling pathways
ZNFX1, miR-150-5p, EIF4E
TP63, SOX2, EGFR, ETV4, TXNRD1, CDK4, YES1, PAK4, HMGA1
miR-204-5p
miR-365, RGS2, cyclin D1, Ecadherin, N-cadherin, vimentin c-Myc
miR-138, EZH2, vimentin, Ncadherin, ZEB1, E-cadherin
P53
Bax protein, Bcl-2 protein
CEBPA, Bcl2
miR-675, Slug, HuR, EGR1
Hep-2, iNOE Tca8113 and Cal27, hNOK
YAP1, miR-375
miR-140-5p, PAK1, miR-503, miR-96 miR-184, SF1, caspase-3, Bax protein, BCL2
Gene interaction
NHOKs, Tca8113, SCC-2, SCC4, SCC-9, and Cal-27 Tca8113, SCCA, CAL-27, SCC9, NHOK, Tca8113-CDDP and TSCCA-CDDP AMC-HN-8 and Hep-2
Assessed cell line
-
Poor prognosis
Poor prognosis
-
-
Poor prognosis
-
-
Poor prognosis
Poor prognosis
Poor prognosis
Poor prognosis
Poor prognosis, lymph node metastases Poor prognosis, lymph node metastasis Poor prognosis
Poor prognosis
-
-
Association with patient outcome
(Li et al., 2019d)
(Kong et al., 2019) (Kou et al., 2019) (Li et al., 2013)
(Kong et al., 2014)
(Kolenda et al., 2019)
(Huang et al., 2019b) (Jiang et al., 2018)
(Huang et al., 2019a)
(Huang et al., 2018)
(Han et al., 2018) (Hong et al., 2019) (Hong et al., 2018)
(Guo et al., 2018)
(Guan et al., 2016)
(Gao et al., 2018)
(Zhu et al., 2019) (Fang et al., 2017)
Ref.
(continued on next page)
Cell apoptosis, invasion, tumor Growth Cell proliferation, invasion, migration, tumor growth
Cell growth, migration, and invasion Cell migration and invasion
Cell proliferation, invasion, apoptosis, cell cycle control, EMT Cell viability, colony formation, resistance to chemo- and radiotherapy Cell proliferation, migration and invasion Cell-cycle regulation, chromatin binding, cell proliferation, survival, metastasis EMT, proliferation, migration, invasion, apoptosis, cell adhesion, signal transduction, differentiation, angiogenesis, oxidative stress response EMT and cell migration
Cell proliferation, migration and invasion, Tumor growth
Cell proliferation, apoptosis, radio resistance of HNSCC Cell proliferation, apoptosis
Cells proliferation, apoptosis, migration and invasion
Cell proliferation, migration, and invasion, tumor growth Cell proliferation, CDDP sensitivity in OSCC, Tumor growth Cell proliferation, migration and invasion apoptosis, tumor growth, metastasis Cell proliferation, viability, migration, invasion
Functions
S. Ghafouri-Fard, et al.
Experimental and Molecular Pathology 112 (2020) 104353
5
Oral SCC
Oral SCC
Oral SCC
Oral SCC
Oral SCC
Oral SCC
Oral SCC
FTH1P3
TUG1
NEAT1
HNF1A-AS1
MINCR
CCAT2
Oral SCC
TUG1
ANRIL
Laryngeal SCC
snaR
Oral SCC
Tongue SCC
TUG1
HOTAIR
Laryngeal SCC
External auditory canal SCC
Tongue SCC
ADAMTS9AS2 SNHG20
lnc-MMP3-1
Oral SCC
AC132217.4
Tongue SCC
Oral SCC
SNHG16
CILA1
Oral SCC
LINC00152
Laryngeal SCC
Oral SCC
OIP5-AS1
SNHG1
Cancer subtype
Gene
Table 1 (continued)
62 paired OSCC tissues and ANTs
62 pairs of OSCC tissues and their ANTs OSCC tissues and paired ANTs
58 OSCC and ANTs
BALB/c thymic free nude mice
134 patients
56 tissue and serum samples
-
8 pairs of cancerous and ANTs
155 patients; BALB/c-nu mice
20 pairs of carcinoma tissues and ANTs
56 pairs of LSCC tissues and ANTs 27 samples of fresh TSCC tissues and ANTs 52 patients with LSCC and 38 healthy volunteers 96 OSCC tissues and matched ANTs
Tca8113, Cal27, and hNOK
CAL-27, HN5, SCC-15, SCC-9, Tca8113, NHO TSCCA, Tca8113, SCC25, HOK
HN4, Tca-8113, UM-SCC-1, Cal-27, SCC-25, SCCKN, hNOK
SNU1041, SCC25, SCC4, SCC9, hNOK NOK, SCC-4, SCC-9, SCC-25, CAL-27, HN-6, and TCA8113
SCC15, TW2.6
Tca8113
-
CAL27 and SCC9
HEp-2
NHOK, SCC-25, CAL-27, Tca8113, and TSCCA
UM-SCC-17A
CAL-27 and SCC-9
Cal27, SCC9, SCC15, SCC25 and SCC4, NOKs AMC-HN-8 and Hep-2
UM-SCC6, UM-SCC6H, SCC090
SCC-25, CAL-27, NHOK
SCC9, SCC15, Ca9-22, HSU3, NHOK Tca8113, OSCC-15, SCC-9, and SCC-25, hNOKs
SCC4, SCC9, SCC25, FaDu, Cal27, HOK
73 tumor specimens with paired ANTs
38 pairs OSCC tissue samples ANTs, BALB/c nude mice 40 OSCC tissues and corresponding ANTs; BALB/c nude mice 29 pairs of OSCC tissues and normal tissues; Balb/c-nude mice 30 OSCC tissues and normal tissues; Four-week-old nude mice 76 TSCC specimens
Assessed cell line
Samples
STAT3, Jagged-1/Fc, Notch1 and Hes1 β-catenin, cyclin D1, Ecadherin, N-cadherin and cmyc
miR-365, MMP-2, MMP9
miR-524-5p, DLX1
-
Active caspase-3
p53, p21
β-catenin, cyclin D1, cmyc, LiCl, cleaved caspase-3 and caspase-9, Bax, Bcl-2 Bax, Bcl-2, cleaved Caspase-9, cleaved PARP, MMP-2 and MMP-9 E-cadherin, vimentin, Wnt5A, b-catenin, GSK-3b, c-Myc, survivin -
TGF-β1
-
miR-600, EZH2, E-cadherin, vimentin miR-140
c-Myc, PCNA, MMP-2, MMP-9, E-cadherin, N-cadherin, Snail, has-miR-124-3p IGF2, KLF8
miR-139-5p, N-cadheri, Vimentin, E-cadherin
miR-338-3p, NRP1
WWTR1, CD44, CD133, Bmi1, SOX2, E-cadherin, N-cadherin, vimentin, Twist, Slug
Gene interaction
Wnt/β-catenin
Wnt/beta-catenin
Notch
-
PI3K/Akt/GSK3b/ Wnt/bcatenin TUG1/miR-524-5p/DLX1
TGF-β/Smad
Pathways in cancer, PI3KAkt signaling pathway and focal adhesion -
Wnt/b-Catenin
Poor prognosis
Poor prognosis
Poor prognosis, lymph node metastasis Poor prognosis
Poor prognosis, TNM stage -
-
-
Poor prognosis, TNM stage
Poor prognosis
TNM stage, lymph node metastasis, tumor grade Poor prognosis and metastasis
Wnt/β-catenin Mitochondrial apoptotic pathway
Poor prognosis
-
Poor prognosis
Poor prognosis
-
-
Poor prognosis
Unfavorable prognosis, tumor size, cervical node metastasis -
Association with patient outcome
-
-
-
miR-600/EZH2
KLF8/AC132217.4/IGF2
-
-
miR-338-3p/NRP1
Signaling pathways
(Ma et al., 2017b)
(Liu et al., 2019c) (Lyu et al., 2019)
(Liu et al., 2018b)
(Liu et al., 2016) (Liu et al., 2019a) (Liu et al., 2018a) (Liu et al., 2019b)
(Liu et al., 2017a)
(Lin et al., 2018b)
(Lin et al., 2018a)
(Li et al., 2019e) (Liu et al., 2019c) (Liu et al., 2017b) (Liang et al., 2019) (Liang et al., 2017b)
(Li et al., 2017)
(Li et al., 2019c)
(Li et al., 2019b) (Li et al., 2018)
(Li et al., 2019a)
Ref.
(continued on next page)
Cell proliferation, migration, EMT, apoptosis Cell proliferation, migration, cell cycle progression, apoptosis, metastasis Cell proliferation, invasion, inhibiting and apoptosis
Cell proliferation, apoptosis and cell cycle Cell proliferation and apoptosis Cell proliferation, migration and invasion Migratory, proliferative potentials, cell-cycle progression Cell migration and invasiveness
Differentiation degree, tumor invasion
Cell carcinoma proliferation, migration and EMT Cell Proliferation and tumor stage Apoptosis, cell proliferation, cell cycle Cell proliferation, migration, and invasion Cell growth, cell proliferation, cell invasion, colony formation, apoptosis Cell proliferation, invasion, migration, apoptosis, colony formation, EMT Metastasis, EMT, ChemoResistance, cell viability
Cell proliferation, migration and invasion, tumor growth Cell proliferation, colony formation, migration, invasion, EMT, tumor growth Cell proliferation, migration and invasion, cell cycle, apoptosis, tumor growth Metastasis, cell migration and EMT
Cell proliferation, migration, invasion, apoptosis
Functions
S. Ghafouri-Fard, et al.
Experimental and Molecular Pathology 112 (2020) 104353
HNSCC
Laryngeal SCC
Tongue SCC
Oral SCC
Tongue SCC
Laryngeal SCC
SOX2-OT
MPRL
LACAT1
UCA1
HOTAIR
HOXA11-AS
PCAT-1
Laryngeal SCC
RHPN1-AS1
Laryngeal SCC
HNSCC
ST7-AS1
UCA1
Hypopharyngeal SCC Laryngeal SCC
UCA1
Oral SCC
Cutaneous SCC
PICSAR
PDIA3P
Tongue SCC
TUC338
HNSCC
HNSCC
ANRIL
CASC9
Cancer subtype
Gene
Table 1 (continued)
6
-
87 patients
23 patients, BALB/c nude mice
90 patients and 90 healthy subjects 23 paired cancer tissues and ANTs, athymic nude mice 65 LSCC tissues and paired ANTs; BALB/c nude mice
58 patients
32 tumor and 12 ANTs, 66 tumor and 56 ANTs
25 paired cancerous and ANTs
26 patients
Tissue samples of SCC tumors (n=6) and normal skin (n=7), Tissue microarrays consisting of samples from normal sunprotected skin (n=9), actinic keratosis (n=26), SCC in situ (n=20), and SCC (n=21); 53 patient tumors and paired ANTs
25 pairs of tumor and ANTs
-
Samples
-
Fadu, SCC-25, CAL-27, Tca8113, Hs 680.Tg CAL 27, SCC-9
CAL-27, SCC-9 and SCC-25
Cal27, NOK, JHU029 and JHU022 HEp-2 and SCC10A
UM -SCC 10A/ B, −11B, −14A/ B, −17A/ B, −47, −104, UT -SCC -14, −24A/ B, − 33, UD -SCC 1, − 2, − 3, − 5, − 6, −7A, − 8, FaDu, HaCaT, VM-CUB1, SW-1710, HT-1376, 5637, BFTC-905, HBLAK SCC4, SCC9, SCC1, SCC25, TU183, HSU3, FADU, OEC-M1, SNU1041, SCC15, NHOK AMC-HN-8
AMC-HN-8 and Hep-2
Cal-27 and Tca8113
TU-212, Hep-2 and NP-69
FaDu
NHEKs, cSCC cell lines
CAL-27 and SCC-9
FaDu, CAL27
Assessed cell line
CD63
-
microRNA-4301
miR-483-5p
Caspase 9, PARP, c-Myc, ASK1and AKT1 PTEN, EZH2
GSK-3β
miR-185-5p, Ki-67, CCND2, Cyclin D2
E-Cadherin, BCL2
β-Catenin, Claudin-1 and Vimentin -
CARM1, Sox-2
-
DUSP6, MMP13, Ki-67, p38α and p38δ
-
PI3K/Akt
-
-
SOX2-OT–EZH2–PTEN
c-Myc/AKT1/p38 MAPK
Wnt/β-catenin
miR-185-5p/CCND2
-
-
-
ST7-AS1/CARM1/Sox-2
-
ERK1/2, ERK/MAPK
-
-
β-catenin, CCND1, MYC, GSK3β, glycogen synthase kinase 3 beta ARF mRNA, p15 and p16 -
Signaling pathways
Gene interaction
-
Poor prognosis
Good prognosis
-
Poor prognosis
Poor prognosis
Poorer prognosis
Poor prognosis, neck nodal metastasis, and clinical stage Poor prognosis
Poor prognosis
Significantly worse prognosis Poor prognosis
-
-
-
Association with patient outcome
(Wang et al., 2019a) (Wang et al., 2016a)
(Tian et al., 2019)
(Sun et al., 2019) (Sur et al., 2019) (Tai et al., 2019)
(Sun et al., 2017)
(Sassenberg et al., 2019)
(Qiu et al., 2019) (Qu et al., 2018)
(Qian et al., 2017) (Tai et al., 2019)
(Matsunaga et al., 2019) (Ouyang et al., 2017) (Piipponen et al., 2016)
Ref.
(continued on next page)
Chemo resistance, apoptosis, cisplatin-induced PI3K activity, activation phosphorylation of Akt
Cell proliferation, invasion and migration Tumor growth, apoptosis, cell proliferation Cell proliferation, migration, invasion, cell apoptosis, tumor volume and tumor weight Mitochondrial fission, cisplatin sensitivity, apoptosis, growth Cell proliferation, Apoptosis
Cell proliferation
Cell proliferation, migration and invasion, chemo resistance
Cell proliferation, invasion, apoptosis, metastasis TNM stages, metastasis, migration, tumor sphere formation Cell Migration, Invasion and Proliferation, EMT, apoptosis Cell growth, migration, and invasion
Cell proliferation, regulation of G1 phase progression Cell proliferation and apoptosis Cell proliferation and migration
Functions
S. Ghafouri-Fard, et al.
Experimental and Molecular Pathology 112 (2020) 104353
31 OSCC tumor tissues and ANTs, BALB/c nude mice
-
Laryngeal SCC
HNSCC
Oral SCC
Oral SCC
Oral SCC
Tongue SCC
Oral SCC
Oral SCC
Laryngeal SCC
Oral SCC
Laryngeal SCC
HNSCC
HNSCC
Oral SCC
Oral SCC
Laryngeal SCC
HNSCC
Oral SCC
MIR31HG
(Wang et al., 2019b)11AS HOTAIR
lnc-p23154
AFAP1-AS1
HOTAIR
SNHG20
7
H19
HOTAIR
XIST
MYOSLID
HuR
LINC00662
FEZF1-AS1
RGMB-AS1
LINC00460
TUG1
42 pairs of OSCC tissues and ANTs 49 paired LSCC tissues and ANTs, nude mice 54 HNSCC tissues and their ANTs
34 Tumor tissues and ANTs; BALB/c mice 15 paired fresh cancer tissues and ANTs, 502 cases of HNSCC and 44 ANTs 73 pairs of HNSCC paraffinembedded tissue samples TSCC samples and ANTs
12 pairs of OSCC patients and matched ANTs; 4-week-old mice 5 matched samples of LSCC tissues and ANTs, 82 matched cancerous and ANTs, BALB/c mice 76 OSCC samples and ANTs
103 pairs of human TSCC tissues and corresponding ANTs, BALB/c athymic nude mice 50 tumor and ANTs
49 OSCC and ANTs, BALB/c nude mice
52 LSCC patients and 49 patients with polyps of vocal cords 52 Pairs of tumor tissues and ANTs; BALB/c mice 60 patients; Nude mice
NEAT1
Samples
Cancer subtype
Gene
Table 1 (continued)
PCI-13, FaDu, SCC-15, UMSCC-10A
Hs 680.Tg, Fadu, SCC-25, CAL27 and Tca8113 Hep-2 and AMC-HN-8
SCC25, HN4, Cal27, SCC4, HN30, HN12, HN13 and FaDu HIOEC, CGHNC9, ISG15, SCC9, and SCC25
Tca8113, HIOEC, Cal27, SCC4 and SCC9
Hep-2 and HEK293T
TSCCA, Tca8223, CAL-27, Tb3.1
Hep-2
HIOEC, Tca8113, UM-1 and CAL-27 SCC9, SCC15, SCC25, Ca9-22, HSU3, TSCCA, Fadu, NHOK
SCC-15, Tca8113, SCC-4, SCC9, CAL-27
UM1, HSC-4, HSC-6, NOK, HEK 293T, SCC-15, SCC-25, CAL-27
STC2, miRNA-206, AKT, ERK, Beclin 1, cleaved-PARP, Bax, cleaved- caspase 3 FMNL2, miR-219, FMNL2-WT
miR-22, NLRP3
miR-196a
HOTAIR, miR-7, bcl2l1, bcl3, birc3 and bcl2a1 Wnt3a and β-catenin
Slug, PDPN and LAMB3
EZH2, miR-124
EZH2, E-cadherin, PRC2 complexes
miR-148a-3p, DNMT1
ALDH1, LIN28, Nanog, Oct4, SOX2, miR-197
-
MAP1LC3B, Beclin1, ATG3, ATG7, N –cadherin, vimentin, E–cadherin, caspase 3, caspase 7, Mcl-1, survivin, bcl -2, MDR1 miR-378a-3p, HK2, PKM2, Glut1, LDHA, MMP1, CTGF, N –cadherin, vimentin, E–cadherin SLUG, SNAIL1, VIM, CADN, ZEB1, ZEB2, SMAD2, NANOG, NESTIN, SOX2, TWIST1
miR-214-3p, PIM1
NHOK, TSCCA, CAL-27, SCC-9, Tca8113 KB, CAL -27
s HIF1A, P21, CCND1
CDK6, miR-107
Gene interaction
Fadu, Cal-27
Hep-2
Assessed cell line
TUG1/miR-219/FMNL2
f LINC00460/ miR-206/ STC2, AKT signaling
RGMB-AS1/miR-22/NLRP3
-
Wnt/β-catenin
-
-
miR-124-3p/EZH2
-
H19/miR-148a-3p/DNMT1
SNHG20/miR-197/LIN28
-
Wnt/β-catenin
Glut1-mediated glycolysis
-
HOXA11-AS/miR214-3p/ PIM1
-
miR-107/CDK6
Signaling pathways
Poor prognosis
Shorter overall survival
Poor prognosis
Shorter overall survival Tumor size, stage and lymph node metastasis Poor prognosis
Poor prognosis
-
Poor prognosis
Poorer overall survival
-
Poorer prognosis
Poor prognosis
-
-
-
Poor prognosis
Lymph node metastasis and clinical stage -
Association with patient outcome
(Xu et al., 2019) (Xu and Xi, 2019) (Xue et al., 2019)
(Xu et al., 2016) (Xue et al., 2019)
(Xiao et al., 2019b) (Xiong et al., 2019)
(Wu et al., 2015)
(Xu et al., 2016)
(Wu and Xie, 2015) (Wu et al., 2019)
(Wang et al., 2018f)
(Wang et al., 2018e)
(Wang et al., 2018c)
(Wang et al., 2019b)
(Wang et al., 2016b) (Wang et al., 2018b)
(Wang et al., 2014)
Ref.
(continued on next page)
Cell viability, migration, invasion, metastasis Cell proliferation and migration, invasion, apoptosis Cell proliferation, clinical stage Tumor growth, cell proliferation and invasion Cell cycle, autophagy and apoptosis
Cell invasion proliferation, colony formation and metastasis Cell proliferation, migration, and invasion, tumor growth Cell invasion, migration and metastasis, EMT
Cell growth, cell cycle, and apoptosis Proliferative ability, mammosphere-forming ability, and tumor growth Cell migration, invasion and proliferation
Cell proliferation, invasion and survival, cell cycle arrest
Invasion-metastasis potential, tumor size, cell migration and invasion
Cell proliferation, migration, invasion, autophagy, apoptosis and sensitivity to cisplatin
Proliferation, apoptosis and cell cycle arrest Cell proliferation, cell cycle progression, and cell apoptosis Cell Proliferation, cisplatin resistance
Functions
S. Ghafouri-Fard, et al.
Experimental and Molecular Pathology 112 (2020) 104353
Cancer subtype
Tongue SCC
Laryngeal SCC
Oral SCC
Oral SCC
HNSCC
Tongue SCC
Tongue SCC
Laryngeal SCC
Oral SCC
Oral SCC
Oral SCC
Tongue SCC
HNSCC
Oral SCC
Gene
THOR
LOC554202
CASC9
FAL1
PVT1
LINC00673
LINC00152
FTH1P3
LEF1-AS1
LINC00668
FTH1P3
HOTTIP
ANRIL
PAPAS
Table 1 (continued)
8
49 Fresh HNSCC tissues and ANTs; 6-week-old athymic nude mice
86 TSCC tissues and 14 ANTs
70 patients
50 patients, nude mice
88 pairs of OSCC tumor tissues and ANTs, BALB/c-nu male mice
Set 1: 15 paired primary TSCC tissues and ANTs, Set 2: paraffin-embedded SCC tissue samples from 202 cases of patients Set1: 15 TSCC and 14 nontumor lingual mucous membrane biopsies, Set2: 182 paraffin-embedded TSCC and 46 non-tumor lingual mucous membrane tissue samples, GSE30784: 167 cancer tissues and 45 ANTs, GSE9844: 26 cancer tissues and 12 ANTs 40 Fresh LSCC tissues and ANTs
40 pairs of tumor samples and ANTs Cohort 1: 35 fresh OSCC tissue and matched ANTs, Cohort 2: 84 paraffin-embedded tissue sections, SPF BALB/c nu/nu nude mice 20 pairs of OSCC tissues and ANTs 83 SCCHN and their ANTs; Tu686, FaDu cell lines, Athymic nude mice
SCC090 and SCC25 OSCC
CAL-27, SCC-9, HN4, HN6 and HN30
SCC4, SCC9, SCC1, SCC25, TU183, HSU3, FADU, OEC-M1, SNU1041, SCC15, NHOK SCC4, SCC9, SCC1, SCC25, TU183, HSU3, FADU, OEC-M1, SNU1041, SCC15 and NHOK -
NHOK, SCC9, FADU, SCC25, SCC1, TU183, HSU3, OECM1, SNU1041, SCC4, and SCC15
Hep-2 and TU212
-
Tca8113 and Cal27
HOKs, SCC6, SCC9, SCC25, HN4, and HN6 Tu686, FaDu
HOMEC, SCC15 and CAL27
Hep2
Tca-8113 and Cal-27
HN4, HN6, SCC-25, CAL-27, NHOK
46 tumors and matched ANTs, NOD/SCID mice
55 tongue cancer and 31 ANTs; Athymic nude mice
Assessed cell line
Samples
TGF-β1
miR-125a-3p, ELK1, FGF1, GRB2, NF1, FGFR1 and FGFR2
-
miR-224-5p, fizzled 5
miR-297, ki-67
MST1/2, SAV1, LATS1/2, MOB, YAP, Ki67
Caspase-3
SNHG5, LINC00520, LINC00094, LINC00511, EPB41L4A-AS1, and LINC00341, H19
-
E-cadherin, Vimentin, βcatenin, p-GSK3β,
microRNA-761, CRKL
p-AKT, p-mTOR, P62, BCL-2, BAX and the LC3BII/LC3BI ratio
IGF2BP1, IGF2, CD44, KRAS, Cyclin D1, Cyclin E1, p21 and p27 miR-31, RhoA
Gene interaction
-
ANRIL/miR-125a-3p/ FGFR1/MAPK
-
FTH1P3/miR-224-5p/ fizzled 5
miR-297/ VEGFA
Hippo LEF1-AS1/LATS1/ YAP1
Poor prognosis, T stage, distant metastasis, clinical stage Poor prognosis
Poor prognosis
Poor prognosis
Poor prognosis
Poor prognosis
Poor prognosis
-
-
Poor prognosis
Poor prognosis
Poor prognosis
Poor prognosis
-
Poor clinical outcomes
Association with patient outcome
-
Wnt/β-catenin
microRNA-761/CRKL
AKT/mTOR
-
THOR/IGF2BP1/IGF2-MEKERK
Signaling pathways
(Zhang et al., 2018a)
(Zhang et al., 2015)
(Zhang, 2017b)
(Zhang, 2017a)
(Zhang et al., 2019a)
(Yuan et al., 2019a)
(Yu et al., 2017b)
(Yu et al., 2017a)
(Ye and Jiao, 2019) (Yu et al., 2018)
(Yang et al., 2018) (Yang et al., 2019b)
(Yang et al., 2019b)
(Yan et al., 2017)
Ref.
(continued on next page)
Cell invasion and migration
Cell cycle, proliferation, tumor growth
Cell proliferation and colony formation
Cell proliferation, migration and invasion, apoptosis, lymph node metastasis Cell survival, proliferation and migration, apoptosis, tumor growth and cell cycle arrest Cell proliferation, tumor growth
Tumor size, invasion of muscles, lymph node metastasis, and recurrence
Cell proliferation and invasion, cervical lymph node metastasis, EMT, stemness Cell invasion, metastasis, tumor size
Proliferative potential
Cell growth, cell cycle and cell invasion Apoptosis, autophagy, tumor size, regional lymph node metastasis, cell proliferation
Cell proliferation, migration, invasion, cell cycle arrest, tumor growth, metastasis Cell proliferation
Functions
S. Ghafouri-Fard, et al.
Experimental and Molecular Pathology 112 (2020) 104353
Cancer subtype
Tongue SCC
Laryngeal SCC
Hypopharyngeal SCC
Laryngeal SCC
Laryngeal SCC
Tongue SCC
Oral SCC
Tongue SCC
HNSCC
Tongue SCC
Gene
KCNQ1OT1
LINC00668
PEG10
HOTAIR
PVT1
MIAT
HAS2-AS1
CASC15
HOTAIR
UCA1
Table 1 (continued)
9
124 TSCC tissues and paired normal tissue
-
30 TSCC samples and ANTs
96 OSCC tissues and paired normal mucosa, Nude mice
30 LSCC and corresponding ANTs 116 TSCC patients
40 LSCC tissue samples and ANTs
56 patients
24 paired-specimens
68 patients with OSCC and 52 healthy volunteers 95 ANTs and 102 TSCC tissues; BALB/c nude mice
Samples
SCC9, SCC15, SCC25, Cal27, and Tca8113
SCC1, SCC4, Cal27, UM1, NOK16B, NHOK Tca8113, Tca8113P160, Tb3.1, Tscca, Hep-2
SCC-9 and CAL-27
NHBEC, TU686, TU177, and LSC-1 SCC-9
Hep-2, AMC-HN8
FaDu
TU177, TU212, TU686 and AMC-HN-8
CAL27 and SCC9
Assessed cell line
MICU1, Bcl-2, BAX, Caspase-3, Cleaved Caspase-3, Cytochrome c MAPK/Erk1/2, p-MAPK/Erk1/ 2, AKT1/2, and p-AKT1/2, bcatenin, TCF-4, cyclin D1
miR-33a-5p, ZEB1, cyclin D1
E-cadherin, vimentin, βcatenin, N-cadherin, and SNAI1 Ki-67, E-cadherin, vimentin, p65 KD, HF-1α and NF-κB
miR-519d-3p
EZH2
-
hsa-miR-197-3p, hsa-miR-761, hsa-miR-204- 5p, hsa-miR211-5p, hsa-miR-134-5p, cleaved PARP and cleaved caspase-3, -7, and -9 ABL2, RAB3B, ENAH and HMGA2
Gene interaction
WNT/b-catenin
Mitochondrial apoptotic pathway
-
-
Wnt/β-catenin
-
-
-
-
Ezrin/Fak/Src
Signaling pathways
Lymph node metastasis, apoptosis, TNM Stage
Poor prognosis
-
Poor prognosis, cervical lymph node metastasis -
-
-
-
-
Low overall survival rate Poor prognosis
Association with patient outcome
Proliferation
Hypoxia-induced invasiveness, lymph node metastasis Cell proliferation, cycle, and migration Mitochondria Related Apoptosis, Tumor Growth
Cell proliferation, migration and invasion, cervical lymph node metastasis Cell proliferation, invasion and metastasis, tumor size, tumor node metastasis Cell proliferation and cisplatinum resistance, lymphatic metastasis Cell proliferation and migration, apoptosis Cell invasion, EMT
Cell proliferation and cisplatin resistance
Functions
(Yang et al., 2016b)
(Zuo et al., 2018) (Kong et al., 2015)
(Zhu et al., 2017)
(Zheng et al., 2019) (Zhong et al., 2019)
(Zheng et al., 2017)
(Zhao et al., 2017b)
(Zhao et al., 2019)
(Zhang et al., 2019c) (Zhang et al., 2018b)
Ref.
S. Ghafouri-Fard, et al.
Experimental and Molecular Pathology 112 (2020) 104353
122 patients and 52 healthy controls
40 paired OSCC and ANTs
69 Paired tumor specimens and their ANTs, athymic BALB/c nude mice
40 paired OSCC and ANTs
Oral SCC
Oral SCC
Oral SCC
Oral SCC
CASC2
10
HNSCC
Laryngeal SCC
Oral SCC
Oral SCC
lnc-IL17RA-11
PTCSC3
SOX21-AS1
GAS5
Oral SCC
Laryngeal SCC
Oral SCC
AC026166.2-001
45 Fresh OSCC tissues and normal control tissues
Oral SCC Oral SCC
LOC441178 MEG3
Oral SCC
BALB/c nude mice
Oral SCC Oral SCC
MORT LINC01133
C5orf66-AS1
Tumor tissue and ANTs from 59 patients 50 pairs of tissue samples with paired ANTs 52 patients 83 tumor samples and ANTs
Tongue SCC
FALEC
66 LSCC patients and 52 healthy volunteers Paired tumors and ANTs from 2 OSCC patients -
-
BALB/c nude mice
30 paired OSCC and ANTs
96 paraffin-embedded TSCC samples and 10 paired TSCC and matched ANTs; NOD/SCID mice 17 pairs of fresh TSCC tissues and ANTs; 8week-old male mice
Tongue SCC
NKILA
350 patient and 44 controls
Oral SCC
AC012456.4
Cancer samples and ANTs from 62 patients
Laryngeal SCC
NEF
Samples
Cancer subtype
Gene
HSC3, HSC6, SCC15, SCC25, cal-27, UM1
SAS, CAL27
SCC-47, SCC-104, SAS UM-SCC-17A
AMC-HN-8, TU-212
HIOEC, SCC25, CAL27, HB, Tca8113 SCC 9, HOK
H157 and HSC-2, and HEK-293
SCC-9, CAL-27, SCC25, SCC-4, SCC-6, SCC-15 SCC090, SCC25 NOK, CAL2, HN4, and 293FT SCC-25 SCC15 and Cal27
CAL27 Tca8113
Tca8113, TSCCA, CAL-27, SCC-9, HOK Tca8113, SCC-9, TSCCa, CAL-27, NOK Tca8113, TSCCA, CAL-27, SCC-9, NHOK -
SCC090, SCC25
UM-SCC-17A
Assessed cell line
E-cadherin, fibronectin, cyclin D1 miR-21, PTEN, Akt, E-cadherin, PCNA, cyclinD1, Ki-67, Ncadherin, vimentin, snail1
HOTAIR, STAT3
ER-α, CDK2, CCNA2, PCNA
CYC1, Bcl-2, Bax, cleaved Caspase-3/7/9, MMP9 miR-24-3p, p27 and cyclin D1
miR-21
miR-548d-3p, SOCS5, SOCS6
ROCK1, HIF-1α β-catenin, TCF-4 and cyclin D1
ROCK1 GDF15, MMP10, and MMP13
NF-κB, IκBα, Bay-117082, JSH23, E-cadherin, N-cadherin and vimentin, p65 EZH2, ECM1
-
CDK1
microRNA-21, PDCD4, Bax, Bcl2
CDK1
miRNA-21
-
Gene interaction
Table 2 Function of down-regulated lncRNAs in HNSCC (ANT: adjacent normal tissue, EMT: epithelial-mesenchymal transition).
miR-21/PTEN
-
-
P53
miR-24-3p/p27
-
miR-548d-3p/ JAK-STAT miR-548d-3p/ SOCS5/SOCS6 -
RhoA/ROCK WNT/β-catenin
-
-
CALCIUM, MAPK, JAK/ STAT NF-κB/Twist
-
CASC2/miR-21/ PDCD4
-
-
Wnt/β-catenin
Signaling pathways
-
Poor prognosis
-
disease prognosis
Poor prognosis
-
Poor prognosis
-
Poor prognosis -
Poor prognosis -
Good prognosis
Poor prognosis
Poor prognosis
-
-
-
-
Poor prognosis
Association with patient outcome
(Song et al., 2019) (Xiao et al., 2019a) (Yang et al., 2016a) (Zeng et al., 2019)
(Shen et al., 2018)
(Lu et al., 2018)
(Zhang et al., 2018a)
(Jin et al., 2019) (Kong et al., 2018) (Xu et al., 2018) (Liu et al., 2017b) (Tan et al., 2019)
(Jia et al., 2019)
(Huang et al., 2016)
(Wang et al., 2018d)
(Xing et al., 2019)
(Cui et al., 2019b) (Dong and Wu, 2019) (Xing et al., 2019) (Piipponen et al., 2016)
Ref
(continued on next page)
Cell growth and invasion, tumor size Cell proliferation, migration, invasion, and EMT
Cell proliferation, invasion, migration, growth, metastasis Cell proliferation, migration, clone-forming capacity, apoptosis DNA replication, cell cycle, base excision repair cell proliferation
Cell cycle, proliferation, migration
Cell proliferation cell migration and invasion, metastasis Cell invasion and migration Cell Proliferation, apoptosis, metastasis Cell migration, apoptosis
Cell migration and invasion, EMT, tumor size, lymph node metastasis Cell proliferation, migration, colony formation, metastasis
Regulation of cell activation
Cell growth, migration and invasion
Cell growth, migration and invasion Cell proliferation, apoptosis, lymph node metastasis
Cell proliferation, Tumor size
Cell proliferation, Apoptosis
Functions
S. Ghafouri-Fard, et al.
Experimental and Molecular Pathology 112 (2020) 104353
Experimental and Molecular Pathology 112 (2020) 104353
Ref
(Zhao et al., 2017a) (Zhou et al., 2016) Cell proliferation, migration and invasion, apoptosis, EMT Cell proliferation, invasion, growth, metastasis, apoptosis Poor prognosis
Poor prognosis
Signaling pathways
AKT
-
Gene interaction
CDH1, miR-205-5p, E-cadherin, Snail2 and vimentin SNU899 and SNU46
FaDu
51 patients
global profiling: 3 paired primary cancerous and ANTs, confirmation: 20 HSCC specimens and ANTs, 138 HSCC patients
Cancer subtype
Laryngeal SCC
Hypopharyngeal SCC
Gene
RP11-169D4.1
AB209630
Table 2 (continued)
Samples
Assessed cell line
Association with patient outcome
Functions
S. Ghafouri-Fard, et al.
identified 728 lncRNAs with differential expression between these two sets of samples. Notably, expression patterns of 55 lncRNAs were associated with survival of patients (Nohata et al., 2016). Through analyzing RNA-sequencing data of 422 HNSCC patients, Zou et al. have identified 276 intergenic lncRNAs whose expression profile predicted overall patients' survival (Zou et al., 2016). 5. Diagnostic value of lncRNAs in HNSCC Dysregulation of expression of lncRNAs in HNSCC tissues and peripheral blood potentiates them as diagnostic biomarkers in this type of cancer. Yao et al. have assessed overall lncRNA signature in both tumoral and peripheral blood samples of HNSCC patients using microarray and RNA-seq methods. They demonstrated differential expression of 432 lncRNAs in peripheral blood samples and 333 lncRNAs in tissues samples. Among these lncRNAs, HOXA11-AS, LINC00964 and MALAT1 showed significant up-regulation in the plasma of HNSCC patients compared with in healthy subjects with combined areas under the curve values of 0.925 and 0.839 in training and validation sets, respectively. So, their study suggested these three lncRNAs as putative diagnostic markers for HNSCC (Yao et al., 2018). Notably, only 12 lncRNAs were common between tumoral tissues and plasma samples (Yao et al., 2018). This finding is in accordance with a previous study which showed expression of HOTAIR, HULC, MALAT1, MEG-3, NEAT-1 and UCA1 in tissues from patients with oral SCC, but only two of these lncRNAs were detectable in saliva samples (Tang et al., 2013). 6. Putative therapeutic implications Animal studies have verified the role of several lncRNAs in the pathogenesis of HNSCC. Knock-down experiments have also shown decreased tumorigenic potential of cancer cell lines after silencing certain lncRNAs. For instance, Wang et al. have made a subcutaneously implanted tumor model in the nude mice after silencing MIR31HG in SCC cells. They reported decreased tumor volume and weight in the lncRNA-silenced group compared with controls (Wang et al., 2018b). Other knock-down assays verified potential use of siRNA-mediated lncRNA silencing in animal models. Experiments in a murine model of metastasis have shown the effects of MALAT1 knock down in decreasing number and size of tumor nodules. Moreover, suppression of MALAT1 using antisense oligonucleotides led to a significant decrease in metastasis (Sun and Ma, 2019). On the other hand, forced over-expression of tumor suppressor lncRNAs have resulted in decreased malignant behavior of implanted cancer cells in animal models (Ma et al., 2019). However, such experiments have not been validated in clinical settings. 7. Discussion Recent methods of lncRNA profiling have easily detected expression of lncRNAs in body fluids and tissues using simple molecular methods (Zhan et al., 2018; Yan et al., 2017). Such advances facilitate application of lncRNAs as biomarkers for early diagnosis of HNSCC or followup of patients after surgical removal of tumoral tissues or chemoradiation. Mechanistically, lncRNAs influence important signaling pathways and cellular processes such as cell proliferation, apoptosis and cell cycle progression. In addition to these processes, certain lncRNAs such as lnc-IL17RA-11 contribute in DNA repair mechanisms (Song et al., 2019). Many of dysregulated lncRNAs in HNSCC are among those with acknowledged roles in other types of cancers. Although this finding further approves their contribution in tumorigenesis, it complicates design of specific diagnostic panels for HNSCC. The most probable mechanism of lncRNA function in carcinogenesis is ceRNA role. A recent study has assessed lncRNA–mRNA interactions according to shared miRNAs between lncRNA–miRNA intersections and miRNA–mRNA interactions. Based on their results, ‘Chemokine signaling pathway’, ‘Focal adhesion’, ‘MAPK signaling pathway’, and 11
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‘Regulation of actin cytoskeleton’ have been among pathways controlled by competitive lncRNAs in oral SCC (Yang et al., 2019c). Such interactions with critical pathways in carcinogenesis potentiate lncRNAs as appropriate therapeutic targets for HNSCC. Based on the fundamental role of HPV in the carcinogenesis process of HNSCC, it is expected that oncoproteins of this virus represent targets of lncRNAs. However, only few studies have addressed association between lncRNAs profile and HPV load/ positivity. So, a future perspective of this research area is clarification of the functional interaction between lncRNAs and viral oncoproteins. The diagnostic power of lncRNAs in HNSCC has been assessed in few studies. The most promising results have been emerged for combination of HOXA11-AS, LINC00964 and MALAT1. Inclusion of other lncRNAs in such panels might increase sensitivity and specificity of these panels and suitability for diagnosis in a wider range of patients. Future studies are needed for this purpose. It is worth mentioning that SCC tumors from different anatomical sites might have distinct expression patterns of lncRNAs (Zou et al., 2015). Such finding complicates design of diagnostic panels and development of targeted therapeutic options. Meanwhile, it necessitates personalized approaches for both mentioned fields. Another forthcoming area of research is contribution of lncRNAs in determination of response of HNSCC patients to therapeutic options. MPRL, UCA1, KCNQ1OT1, HOTAIR and HOXA11-AS have been among lncRNAs whose expression levels might determine response of patients to cisplatin (Zhang et al., 2018b; Fang et al., 2017; Tian et al., 2019; Wang et al., 2019b; Wang et al., 2018c). However, based on the role of lncRNAs in the determination of several aspects of cancer cells fate, this list is expected to include several other lncRNAs as well. Differential expression of lncRNAs between radioresistant and parental nasopharyngeal carcinoma cell lines also implies contribution of these transcripts in conferring radioresistance (Zou et al., 2016). Consistent with the proposed role of lncRNAs in determination of response to therapies, cell line studies have shown alteration of lncRNA expression after irradiation or chemoexposure (Guglas et al., 2018). Taken together, lncRNAs are involved in the regulation of expression of several molecules and signaling pathways which participate in HNSCC. This kind of involvement potentiates them as biomarkers and therapeutic targets. This field is evolving, so it is expected that future therapeutic options would be designed to target lncRNAs-associated pathways.
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